CN111247138A

CN111247138A - Ether compound and use thereof

Info

Publication number: CN111247138A
Application number: CN201880067990.7A
Authority: CN
Inventors: 凯尔·W·H·陈; 保罗·E·尔德曼; 利亚·丰; 大卫·亚伦·赫克特; 弗兰克·默丘里奥; 罗伯特·沙利文
Original assignee: BioTheryX Inc
Current assignee: BioTheryX Inc
Priority date: 2017-08-25
Filing date: 2018-08-07
Publication date: 2020-06-05
Also published as: JP2020531481A; EP3672955A1; US20190062320A1; TW202222794A; US10513515B2; US10927104B2; TW201919639A; AU2018321567A1; TWI742303B; WO2019040274A1; CA3072543A1; US20200231582A1

Abstract

The present invention provides compounds that modulate protein function to restore protein homeostasis and/or cell-cell adhesion. The invention provides methods of modulating protein-mediated diseases, such as cytokine-mediated diseases, disorders, conditions, or responses. Compositions of these compounds are also provided. Methods of treating, ameliorating, or preventing protein-mediated diseases, disorders, and conditions are also provided.

Description

Ether compound and use thereof

Incorporation by reference of any priority application

Any and all applications for which a foreign or domestic priority claim is identified in a request, such as that filed with the present patent application, are hereby incorporated by reference, including U.S. provisional patent application No. 62/550489 filed on 25/8/2017.

Background

FIELD

Compounds, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds to treat, prevent, or diagnose diseases, disorders, or conditions associated with protein dysfunction are provided.

Description of the Related Art

For example, there is a need to dynamically regulate key intracellular signaling proteins within the immune system to maintain the proper balance of proinflammatory mediators or cytokines and anti-inflammatory mediators or cytokines some cytokines promote inflammation (pro-inflammatory cytokines) while other cytokines inhibit the activity of proinflammatory cytokines (anti-inflammatory cytokines), for example, IL-4, IL-10, and IL-13 are potent activators of B lymphocytes and also act as anti-inflammatory agents.

Unregulated activity of these mediators can lead to the development of severe inflammatory states. For example, autoimmune diseases arise when cells of the immune system (lymphocytes, macrophages) become sensitized to "self". Lymphocytes and macrophages are usually under control in this system. However, misdirection of the system to the body's own tissue may occur in response to a trigger that is still unexplained. One hypothesis is that lymphocytes recognize antigens that mimic "self and cascade activation of different components of the immune system occurs, ultimately leading to tissue destruction. It has also been hypothesized that genetic susceptibility contributes to autoimmune disorders.

Overproduction of these cytokines is thought to underlie the progression of a number of inflammatory diseases, including Rheumatoid Arthritis (RA), Crohn's disease, inflammatory bowel disease, multiple sclerosis, endotoxic shock, osteoporosis, Alzheimer's disease, congestive heart failure and psoriasis.

Recent data from clinical trials support the use of protein antagonists of cytokines, such as soluble TNF α receptor fusion protein (etanercept) or monoclonal TNF α antibody (infliximab) to treat rheumatoid arthritis, crohn's disease, juvenile chronic arthritis, and psoriatic arthritis, thus, reduction of pro-inflammatory cytokines such as TNF α, IL-6, and IL-I has become an acceptable treatment for potential drug intervention in these conditions.

In addition, IL-2 is now FDA approved for the treatment of renal cancer and melanoma patients, where long-lasting, complete remission up to 148 months was achieved with IL-2. However, the half-life of IL-2 in serum is short, requiring injection of large amounts of IL-2 to achieve therapeutic levels. Many attempts have been made to minimize the side effects of systemic IL-2 treatment, such as the introduction of IL-2 directly into tumors, but this complicates treatment and is largely unsuccessful.

For a variety of reasons, local delivery of cytokines is attractive as compared to systemic delivery. It exploits the natural biology of cytokines that have been evolved to act locally in a paracrine or autocrine fashion. Local expression also significantly minimizes many of the side effects of systemic delivery of cytokines. Thus, compounds and methods that increase local expression of IL-2 are better tolerated compared to high dose IL-2 treatment, which would expand the therapeutic utility of strategies to increase IL-2.

Other targets include several candidate genes involved in apoptosis and cell survival, including casein kinase 1 α (CK1 α) and zinc finger transcription factors aiolos, helios and ikaros, alolos and ikaros being transcription factors whose expression is restricted to lymphoid lineage.

Likewise, the expression of aiolos in lung and breast cancer is predictive of a significant reduction in patient survival. aiolos reduces expression of a number of adhesion-related genes, disrupts cell-cell and cell-matrix interactions, promotes metastasis. In certain metastatic epithelial cancers, aiolos may also function as an epigenetic driver of lymphocyte mimics. Similarly, aberrant ikaros and helios expression may promote Bcl-XL expression and promote the development of hematopoietic malignancies. Thus, down-regulation of aiolos, ikaros and/or helios may reduce or eliminate metastasis.

Casein kinase 1 α (CK1 α) is a component of the β -catenin degradation complex, a key regulator of the Wnt signaling pathway, whose ablation induces activation of both Wnt and p 53. Schittek and Sinnberg, mol. Cancer.2014,13,231; Cheong and Virshup, J.biochem. Cell biol.2011,43, 465. 469; Elyada et al, Nature 2011,470,409-413. CK1 α phosphorylates β -catenin, which is then further phosphorylated by GSK-3 β. β -catenin is destabilized and labels this protein for ubiquitination and proteasome degradation. CK1 α therefore functions as a molecular switch for the Wnt pathway. Amit et al, Genes 2002,16,1066-1076. CK1 α is crucial for embryogenesis and plays a role in tissue development and response to DNA damage, at least in part with the role of Elaite et al, Gene dev.2002,16,1066-1076. CK 467373, and in part with the role of protein degradation in tissue development and response to DNA damage, Nature, Ser. 2011 53, Cell 19, multilayered protein, Cell strain, III, Ser. No. 3, Ser. 3, et 9, et al.

Indeed, CK1 α also phosphorylates p53, which inhibits binding to MDM2 (a p53 inhibitor) and stabilizes the binding interaction of p53 with transcriptional mechanisms Huart, et al, j.biol.chem.2009,284, 32384-32394.

One mechanism for disrupting protein drivers of disease is to reduce the cellular concentration of these proteins. For example, regulated proteolytic degradation of cellular proteins is critical for normal cellular function. Hijacking (HIJACK) this process provides a new mechanism for treating diseases by targeting specific disease-associated proteins. The irreversibility of proteolysis makes it very suitable as a regulatory switch for controlling unidirectional processes. IKAROS, for example, is a transcriptional repressor of IL-2 expression. Accordingly, a decrease in IKAROS protein levels results in increased IL-2 expression in activated T cells. IL-2 therapy is currently being evaluated for various clinical indications, including for the treatment of Systemic Lupus Erythematosus (SLE), wound healing, and immunooncology.

Summary of The Invention

Some embodiments provide a compound of general formula (I), or a pharmaceutically acceptable salt thereof:

in some embodiments, Q₁Can be CH₂、O、NR₂S or a bond.

In some embodiments, Q₂Can be CH₂Or a key.

In some embodiments, X may be CH₂Or C ═ O.

In some embodiments, X₁May be hydrogen, deuterium, methyl or fluorine.

In some embodiments, ring B may be

Wherein Y is₁Is N or CR_3A，Y₂Is N or CR_3B，Y₃Is N or CR_3C，Y₄Is N or CR_3DAnd Y₅Is N or CR_3E。

In some embodiments, each R is₁May independently be deuterium, hydroxy, halogen, nitro, substituted or unsubstituted amino, substituted or unsubstituted C₁-C₆Alkoxy, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₂-C₆Alkenyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted 3 to 10 membered heterocyclyl, substituted or unsubstituted C₆-C₁₀Aryl, substituted or unsubstituted 5 to 10 membered heteroaryl or L-Y.

In some embodiments, R₂Can be hydrogen, deuterium, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₂-C₆Alkenyl, acyl or- (SO)₂)-C₁-C₆An alkyl group.

In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EEach of which may be independently hydrogen, deuterium, hydroxy, halogen, nitro, substituted or unsubstituted amino, substituted or unsubstituted C₁-C₆Alkoxy, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₂-C₆Alkenyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted 3 to 10 membered heterocyclyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl or L-Y.

In some embodiments, m may be 0, 1,2, or 3.

In some embodiments, n may be 1,2,3, or 4. In some embodiments, n may be 1 or 2.

In some embodiments, L may be-Z₁-(R₄)_t-Z₂–；–Z₁-(R₄-O-R₄)_t-Z₂–；–Z₁(R₄-NH-R₄)_t-Z₂–；–Z₁-(R₄-(NHCO)-R₄)_t-Z₂–；–Z₁-(R₄-(NHC(O)NH)-R₄)_t-Z₂-; or-Z₁-(R₄-(CONH)-R₄)_t-Z₂–。

In some embodiments, Z₁Can be-CH₂NH(CO)–；–NH–；–O–；–CH₂–；–NH(CO)–；–(CO)NH–；–CH₂NH–；–(CO)NHCH₂–；–CH₂CH₂NH–；–NHCH₂-; or-NHCH₂CH₂–。

In some embodiments, Z₂May be-NH-; -O-; -CH₂–；–NH(CO)–；–(CO)NH–；–CH₂NH–；–NHCH₂–；–(CO)NHCH₂–；–CH₂CH₂NH–；–CH₂NH(CO)–。

In some embodiments, each R is₄C which may independently be unsubstituted₁-C₆An alkylene group.

In some embodiments, t may be 1,2,3, 4,5, or 6.

In some embodiments, Y may be

Wherein Y may be derivatized to link to L.

In some embodiments, Y is₁、Y₂、Y₃、Y₄And Y₅At least one of which may be carbon (respectively with R)_3A、R_3B、R_3C、R_3DAnd R_3EA bond, e.g. CR_3A、CR_3B、CR_3C、CR_3DAnd/or CR_3E)。

In some embodiments, when Q₁Can be CH₂Or when a bond is present, then R_3A、R_3B、R_3C、R_3DAnd R_3EOne or more of which cannot be hydrogen. In other embodiments, when R₁When L-Y can be mentioned, R_3A、R_3B、R_3C、R_3DAnd R_3EMay not be L-Y. In still other embodiments, when Q₁When the number is a bond, m is not 0. In some embodiments, when Q₁When is a bond, R₁Is L-Y. In some embodiments, when Q₁Can be a bond, X₁Is hydrogen or methyl, and Q₂Is CH₂When the current is over; then m is not 0. In other embodiments, when Q₁Can be a bond, X₁May be hydrogen or methyl, and Q₂Can be CH₂When the current is over; then R is₁、R_3A、R_3B、R_3C、R_3DAnd R_3EOne of them is L-Y. In some embodiments, when Q₂When can be a bond, Q₁Can be a bond or CH₂。

Some embodiments provide compounds of general formula (I):

or a pharmaceutically acceptable salt thereof, wherein: q₁Is CH₂、O、NR₂S or a bond; q₂Is CH₂Or a bond; x is CH₂Or C ═ O; x₁Is hydrogen, deuterium or fluorine; ring B is

Wherein Y is₁Is N or CR_3A；Y₂Is N or CR_3B；Y₃Is N or CR_3C；Y₄Is N or CR_3D；Y₅Is N or CR_3E(ii) a Each R₁Independently is deuterium, hydroxy, halogen, nitro, substituted or unsubstituted amino, substituted or unsubstituted C₁To C₆Haloalkyl, substituted or unsubstituted C₁-C₆Alkoxy, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₂-C₆Alkenyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted 3 to 10 membered heterocyclyl, substituted or unsubstituted C₆-C₁₀Aryl, substituted or unsubstituted 5 to 10 membered heteroaryl or L-Y; r₂Is hydrogen, deuterium, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₂-C₆Alkenyl, acyl or- (SO)₂)-C₁-C₆An alkyl group; each R_3A、R_3B、R_3C、R_3DAnd R_3EIndependently hydrogen, deuterium, hydroxyl, halogen, nitro, substituted or unsubstituted amino, substituted or unsubstituted C₁To C₆Haloalkyl, substituted or unsubstituted C₁-C₆Alkoxy, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₂-C₆Alkenyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted 3 to 10 membered heterocyclyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl or L-Y; m is 0, 1,2 or 3; n is 1,2 or 3; l is-Z₁-(R₄-O-R₄)_t-Z₂–；–Z₁(R₄-NH-R₄)_t-Z₂–；–Z₁-(R₄-(NHCO)-R₄)_t-Z₂–；–Z₁-(R₄-(NHC(O)NH)-R₄)_t-Z₂-; or-Z₁-(R₄-(CONH)-R₄)_t-Z₂–；Z₁is-NH-; -O-; -CH₂–；–NH(CO)–；–(CO)NH–；–CH₂NH–；–NHCH₂–；–CH₂NH (CO) -or-NHCH₂CH₂–；Z₂is-NH-; -O-; -CH₂-; -nh (co) -; or- (CO) NH-; -CH₂NH–；–NHCH₂-; or-NHCH₂CH₂-; each R₄Independently is unsubstituted C₁-C₆An alkylene group; t is 1,2,3, 4,5 or 6; and Y is

Wherein Y is derivatized to link to L; and wherein Y is₁、Y₂、Y₃、Y₄And Y₅At least one of which is R respectively_3A、R_3B、R_3C、R_3DOr R_3E(ii) a When Q is₁Is CH₂Or when a bond is present, then R_3A、R_3B、R_3C、R_3DOr R_3EIs not hydrogen; when R is₁When L-Y is present, R_3A、R_3B、R_3C、R_3DAnd R_3EEach of which is not L-Y; and when Q₁When the number is a bond, m is not 0.

In some embodiments, X may be CH₂. In some embodiments, X may be C ═ O.

In some embodiments, X₁May be hydrogen. In other embodiments, X₁May be deuterium. In still other embodiments, X₁May be a methyl group. In some embodiments, X₁May be fluorine.

In some embodiments, Q₁May be NR₂. In some embodiments, R₂May be hydrogen. In some embodiments, R₂C which may be substituted or unsubstituted₁-C₆An alkyl group. In some embodiments, R₂May be unsubstituted C₁-C₆An alkyl group. In some embodiments, R₂May be an acyl group. In some embodiments, R₂Can be- (SO)₂)-C₁-C₆An alkyl group. In some embodiments, R₂May be a methyl group.

In some casesIn the embodiment, Q₁Can be CH₂. In some embodiments, Q₁May be O. In some embodiments, Q₁May be S. In some embodiments, Q₁May be a key. In some embodiments, when Q₁When the number is a bond, m is not 0. In some embodiments, Q₂Can be CH₂. In some embodiments, Q₂May be a key. In some embodiments, when Q₂When can be a bond, Q₁Can be a bond or CH₂。

In some embodiments, n may be 1. In some embodiments, n may be 2. In some embodiments, n may be 3. In some embodiments, m may be 1. In some embodiments, m may be 2. In some embodiments, m may be 3. In some embodiments, m may be 0.

In some embodiments, each R is₁May be independently halogen, substituted or unsubstituted amino, substituted or unsubstituted C₁-C₆Alkoxy or substituted or unsubstituted C₁-C₆An alkyl group. In some embodiments, each R is₁May independently be halogen, unsubstituted amino, unsubstituted C₁-C₆Haloalkyl, unsubstituted C₁-C₆Alkoxy or unsubstituted C₁-C₆An alkyl group.

In some embodiments, each R is₁Can independently be fluorine, chlorine, -NH₂、–NH(CH₃)、–N(CH₃)₂、–CF₃、–OCH₃、–OCH₂CH₃、–OCH(CH₃)₂、–CH₃、–CH₂CH₃or-CH (CH)₃)₂。

In some embodiments, ring B may be selected from:

in some embodiments，R_3A、R_3B、R_3C、R_3DAnd R_3EEach of which may be independently hydrogen, deuterium, hydroxy, halogen, nitro, substituted or unsubstituted amino, substituted or unsubstituted C₁-C₆Alkoxy, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₂-C₆Alkenyl, substituted or unsubstituted C₃-C₈A cycloalkyl group, a substituted or unsubstituted 3 to 10 membered heterocyclyl group, a substituted or unsubstituted alkoxyalkyl group, a substituted or unsubstituted cycloalkylalkyl group, a substituted or unsubstituted heterocyclylalkyl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted heteroaralkyl group.

In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EEach of which may be independently hydrogen, hydroxy, halogen, nitro, unsubstituted amino, unsubstituted C₁-C₆Haloalkyl, unsubstituted C₁-C₆Alkoxy, unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₃-C₈A cycloalkyl group, a substituted or unsubstituted 3 to 10 membered heterocyclyl group, a substituted or unsubstituted alkoxyalkyl group, a substituted or unsubstituted cycloalkylalkyl group, a substituted or unsubstituted heterocyclylalkyl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted heteroaralkyl group.

In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EEach of which may be independently hydrogen, hydroxy, halogen, nitro, unsubstituted amino, unsubstituted C₁-C₆Haloalkyl, unsubstituted C₁-C₆Alkoxy, unsubstituted C₁-C₆Alkyl, unsubstituted C₃-C₈Cycloalkyl, unsubstituted 3 to 10 membered heterocyclyl, unsubstituted cycloalkylalkyl, unsubstituted 3 to 10 membered heterocyclylalkyl, unsubstituted aralkyl, or unsubstituted 5 to 10 membered heteroaralkyl.

In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EEach of which may be independently hydrogen, halogen, unsubstituted C₁-C₆Haloalkyl, unsubstituted C₁-C₆Alkoxy, unsubstituted C₁-C₆An alkyl group, an unsubstituted 3 to 10 membered heterocyclyl group or an unsubstituted 3 to 10 membered heterocyclylalkyl group.

In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EOne of which may be halogen, unsubstituted C₁-C₆Haloalkyl, unsubstituted C₁-C₆Alkoxy, unsubstituted C₁-C₆An alkyl group, an unsubstituted 3-to 10-membered heterocyclyl group or an unsubstituted 3-to 10-membered heterocyclylalkyl group, and R_3A、R_3B、R_3C、R_3DAnd R_3EThe others in (a) are hydrogen.

In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EOne of them may be fluorine, chlorine, -CF₃、-OCH₃Unsubstituted C₁-C₆An alkyl group, an unsubstituted 3-to 10-membered heterocyclyl group or an unsubstituted 3-to 10-membered heterocyclylalkyl group, and R_3A、R_3B、R_3C、R_3DAnd R_3EThe others in (a) are hydrogen.

In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EOne of which may be

And R_3A、R_3B、R_3C、R_3DAnd R_3EThe others in (a) are hydrogen.

In some embodiments, one R is₁May be L-Y. In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EOne of which may be L-Y. In some embodiments, Y is₃May be C-L-Y.

In some embodiments, L may be-Z₁-(R₄)_t-Z₂-. In other embodiments, L may be-Z₁-(R₄-O-R₄)_t-Z₂-. In still other embodiments, L may be-Z₁(R₄-NH-R₄)_t-Z₂-. In some embodiments, L may be Z₁-(R₄-(NHCO)-R₄)_t-Z₂-. In some embodiments, L may be-Z₁-(R₄-(CONH)-R₄)_t-Z₂-. In other embodiments, L may be-Z₁-(R₄-(NHC(O)NH)-R₄)_t-Z₂–。

In some embodiments, Z₁Can be-CH₂NH (CO) -. In other embodiments, Z₁May be-NH-. In still other embodiments, Z₁May be-O-. In some embodiments, Z₁Can be-CH₂-. In other embodiments, Z₁May be-NH (CO) -. In still other embodiments, Z₁Can be-CH₂NH-. In some embodiments, Z₁Can be-NHCH₂-. In other embodiments, Z₁May be- (CO) NH-. In still other embodiments, Z₁Can be-NHCH₂CH₂-. In some embodiments, Z₁Can be- (CO) NHCH₂-. In still other embodiments, Z₁Can be-CH₂CH₂NH–。

In some embodiments, Z₂May be-NH-. In other embodiments, Z₂May be-O-. In still other embodiments, Z₂Can be-CH₂-. In some embodiments, Z₂May be-NH (CO) -. In other embodiments, Z₂Can be made into-(CO) NH-. In still other embodiments, Z₂Can be-CH₂NH-. In some embodiments, Z₂Can be-NHCH₂-. In other embodiments, Z₂May be- (CO) NH-. In still other embodiments, Z₂Can be-NHCH₂CH₂-. In some embodiments, Z₂Can be- (CO) NHCH₂-. In other embodiments, Z₂Can be-CH₂CH₂NH-. In still other embodiments, Z₂Can be-CH₂NH(CO)–。

In some embodiments, each R is₄C which may independently be unsubstituted₁-C₄An alkylene group. In some embodiments, each R is₄C which may independently be unsubstituted₁-C₂An alkylene group.

In some embodiments, t may be 1. In some embodiments, t may be 2. In some embodiments, t may be 3. In some embodiments, t may be 4. In some embodiments, t may be 5. In some embodiments, t may be 6.

In some embodiments, the compound of formula (I) is selected from:

or a pharmaceutically acceptable salt of any of the foregoing.

Some embodiments provide a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

Some embodiments provide a method of inhibiting cytokine activity comprising contacting a cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, other embodiments provide a use of a compound of formula (I) or a pharmaceutically acceptable salt of any of the foregoing for inhibiting cytokine activity, comprising contacting a cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt of any of the foregoing, yet other embodiments provide a use of a compound of formula (I) or a pharmaceutically acceptable salt of any of the foregoing for the manufacture of a medicament for inhibiting cytokine activity, comprising contacting a cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt of any of the foregoing.

Some embodiments provide methods of inhibiting aiolos activity comprising contacting a cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Other embodiments provide the use of a compound of formula (I) or a pharmaceutically acceptable salt of any of the foregoing for inhibiting aiolos activity, comprising contacting a cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt of any of the foregoing. Yet other embodiments provide the use of a compound of formula (I) or a pharmaceutically acceptable salt of any of the foregoing for the preparation of a medicament for inhibiting aiolos activity, comprising contacting a cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the cell is a cancer cell.

Some embodiments provide a method of inhibiting ikaros activity comprising contacting a cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Other embodiments provide the use of a compound of formula (I) or a pharmaceutically acceptable salt of any of the foregoing for inhibiting ikaros activity, comprising contacting a cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt of any of the foregoing. Yet other embodiments provide the use of a compound of formula (I) or a pharmaceutically acceptable salt of any of the foregoing for the preparation of a medicament for inhibiting ikaros activity comprising contacting a cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the cell is a cancer cell.

Some embodiments provide methods of inhibiting hellios activity comprising contacting a cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Other embodiments provide the use of a compound of formula (I) or a pharmaceutically acceptable salt of any of the foregoing for inhibiting hellios activity, comprising contacting a cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt of any of the foregoing. Yet other embodiments provide the use of a compound of formula (I) or a pharmaceutically acceptable salt of any of the foregoing for the preparation of a medicament for inhibiting activity of hellios, comprising contacting a cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the cell is a cancer cell.

Some embodiments provide a method of inhibiting CK-1 α activity comprising contacting a cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, other embodiments provide the use of a compound of formula (I) or a pharmaceutically acceptable salt of any of the foregoing for inhibiting CK-1 α activity comprising contacting a cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt of any of the foregoing, yet other embodiments provide the use of a compound of formula (I) or a pharmaceutically acceptable salt of any of the foregoing for the manufacture of a medicament for inhibiting CK-1 α activity comprising contacting a cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt of any of the foregoing.

In some embodiments, the cell is a small cell lung cancer cell, a non-small cell lung cancer cell, a breast cancer cell, a prostate cancer cell, a head and neck cancer cell, a pancreatic cancer cell, a colon cancer cell, a rectal cancer cell, a teratoma cell, an ovarian cancer cell, an endometrial cancer cell, a brain cancer cell, a retinoblastoma cell, a leukemia cell, a skin cancer cell, a melanoma cell, a squamous cell carcinoma cell, an liposarcoma cell, a lymphoma cell, a multiple myeloma cell, a testicular cancer cell, a liver cancer cell, an esophageal cancer cell, a kidney cancer cell, an astrocytic proliferating cell, a relapsed/refractory multiple myeloma cell, or a neuroblastoma cell.

Some embodiments provide a method of treating, ameliorating, or preventing a disease, disorder, or condition associated with a protein selected from the group consisting of cytokines, aiolos, ikaros, helioss, CK1 α, and a combination of any of the foregoing, in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the disease, disorder, or condition is a cancer selected from a hematologic malignancy and a solid tumor. In some embodiments, the disease, disorder, or condition is a cancer selected from small cell lung cancer, non-small cell lung cancer, breast cancer, prostate cancer, head and neck cancer, pancreatic cancer, colon cancer, rectal cancer, teratoma, ovarian cancer, endometrial cancer, brain cancer, retinoblastoma, leukemia, skin cancer, melanoma, squamous cell carcinoma, liposarcoma, lymphoma, multiple myeloma, testicular cancer, liver cancer, esophageal cancer, renal cancer, astrocytosis, relapsed/refractory multiple myeloma, and neuroblastoma.

In some embodiments, the disease, disorder, or condition is selected from inflammation, fibromyalgia, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, uveitis, inflammatory lung disease, chronic obstructive pulmonary disease, and alzheimer's disease. In some embodiments, the disease, disorder, or condition is selected from fibromyalgia, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, crohn's disease, and ulcerative colitis.

In some embodiments, the cytokine is selected from the group consisting of IL-1 β, IL-2, IL-6, and TNF α in some embodiments, the cytokine is TNF α in some embodiments, the protein is aiolos.

Any feature of an embodiment is applicable to all embodiments identified herein. Furthermore, any feature of an embodiment, independently, may be combined in any manner, either in whole or in part, with other embodiments described herein, e.g., one, two, or three or more embodiments may be combined in whole or in part. In addition, any feature of one embodiment may be made optional with respect to other embodiments. Any embodiment of a method may comprise another embodiment of the compound, and any embodiment of the compound may be configured to perform the method of another embodiment.

Brief Description of Drawings

FIG. 1 shows anti-IL-1- β activity in Peripheral Blood Mononuclear Cells (PBMC) seeded in 96-well plates and pre-treated with compound for 1 hour, followed by induction with 100ng/mL LPS for 18 to 24 hours.

FIG. 2 shows anti-IL-6 activity in Peripheral Blood Mononuclear Cells (PBMC) seeded in 96-well plates and pre-treated with compound for 1 hour, followed by induction with 100ng/mL LPS for 18 to 24 hours. Cytokines were measured according to the MesoScale protocol. Negative control wells were treated with DMSO. Compound activity was measured as a percentage of LPS-induced activity.

FIG. 3 shows anti-TNF α activity in Peripheral Blood Mononuclear Cells (PBMC) seeded in 96-well plates and pre-treated with compound for 1 hour, followed by induction with 100ng/mL LPS for 18 to 24 hours cytokine in the medium was measured according to the MesoScale protocol.

FIG. 4 shows anti-CD 3-induced IL-2 secretion in PBMCs. A PBS solution of 1. mu.g/mL anti-CD 3(OKT-3) antibody was plated onto 96-well plates and left overnight at 4 ℃. Approximately 550,000PBMC were added to each well followed by DMSO (control) or compound 1 alone. The induction was measured after 24 hours as fold difference from DMSO stimulated control.

FIG. 5A shows a Western blot of Jurkat cells treated with control (DMSO only) or compound 1 at the indicated concentrations Western blot was performed using RIPA buffer (Pierce) to lyse the cells and using anti-casein kinase 1 α (CK1- α) and anti- β actin antibodies FIG. 5B shows a Western blot of Jurkat cells treated with control (DMSO only) or

compound

1,2,3 or 4 at the indicated concentrations Western blot was performed using RIPA buffer (Pierce) to lyse the cells and performing Western blot using anti-ikaros and anti- β -actin antibodies.

Detailed Description

Some embodiments provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof:

in some embodiments, Q₁Can be CH₂、O、NR₂S or a bond. In some embodiments, when Q₁When the number is a bond, m is not 0. In some embodiments, Q₂Can be CH₂Or a key. In some embodiments, when Q₂When can be a bond, Q₁Can be a bond or CH₂。

In some embodiments, X may be CH₂Or C ═ O. In some embodiments, X may be CH₂. In some embodiments, X may be C ═ O.

In some embodiments, X₁May be hydrogen, deuterium, methyl or fluorine. In some embodiments, X₁May be hydrogen. In other embodiments, X₁May be fluorine. In still other embodiments, X₁May be a methyl group. In some embodiments, X₁May be deuterium.

In some embodiments, ring B may be

Wherein Y is₁Is N or CR_3A；Y₂Is N or CR_3B；Y₃Is N or CR_3C；Y₄Is N or CR_3D；Y₅Is N or CR_3E. In some embodiments, ring B may be selected from:

in some embodiments, ring B is a phenyl group. In other embodiments, ring B is a pyridyl group, such as a 2-pyridyl, 3-pyridyl, or 4-pyridyl group.

In some embodiments, m may be 0, 1,2, or 3. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

In some embodiments, each R is₁May independently be deuterium, hydroxy, halogen, nitro, substituted or unsubstituted amino, substituted or unsubstituted C₁-C₆Alkoxy, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₂-C₆Alkenyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted 3 to 10 membered heterocyclyl, substituted or unsubstituted C₆-C₁₀Aryl, substituted or unsubstituted 5 to 10 membered heteroaryl or L-Y. In some embodiments, R₁May be deuterium. In some embodiments, R₁May be a hydroxyl group. In some embodiments, R₁May be halogen, such as fluorine, chlorine or bromine. In some embodiments, R₁May be a nitro group. In some embodiments, R₁Amino groups which may be substituted, e.g. (C)₁-C₆Alkyl) amino, (3-to 10-membered heterocyclyl) amino or (C)₆-C₁₀Aryl) amino. In some embodiments, R₁May be an unsubstituted amino group. In some embodiments, R₁May be substituted C₁-C₆Alkyl which is unsubstituted C₁-C₆Haloalkyl, for example halomethyl, haloethyl, halo-n-propyl, haloisopropyl, halo-n-butyl, haloisobutyl, halo-sec-butyl, halo-tert-butyl, halopentyl (linear or branched) or halohexyl (linear or branched). In some embodiments, R₁May be unsubstituted C₁-C₆A fluoroalkyl group. In some embodiments, R₁May be unsubstituted C₁-C₆A chloroalkyl group. In some embodiments, R₁May be unsubstituted C₁-C₆Haloalkyl groups including fluorine and chlorine. In some embodiments, R₁C which may be substituted or unsubstituted₁-C₆Alkoxy, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy (linear or branched) or hexoxy (linear or branched). In some embodiments, R₁May be unsubstituted C₁-C₆Alkoxy, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy (linear or branched) or hexoxy (linear or branched). In some embodiments, R₁C which may be substituted or unsubstituted₁-C₆Alkyl radicals, e.g. methyl, ethyl, n-propyl, isopropyl,N-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (linear or branched) or hexyl (linear or branched). In some embodiments, R₁May be unsubstituted C₁-C₆Alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (linear or branched) or hexyl (linear or branched). In some embodiments, R₁C which may be substituted or unsubstituted₂-C₆Alkenyl groups, such as methylene, vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, sec-butenyl, tert-butenyl, pentenyl (linear or branched) or hexenyl (linear or branched). In some embodiments, R₁May be unsubstituted C₂-C₆Alkenyl groups, such as methylene, vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, sec-butenyl, tert-butenyl, pentenyl (linear or branched) or hexenyl (linear or branched). In some embodiments, R₁C which may be substituted or unsubstituted₃-C₈Cycloalkyl radicals, e.g. C₃-C₈Monocyclic cycloalkyl or C₆-C₈Bridged, fused or spiro bicyclic cycloalkyl. In some embodiments, R₁May be unsubstituted C₃-C₈C₈Cycloalkyl radicals, e.g. C₃-C₈Monocyclic cycloalkyl or C₆-C₈Bridged, fused or spiro bicyclocycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, octahydropentalene, decahydronaphthalene, bicyclo [4.2.0]Octane and bicyclo [3.1.1]Heptane. In some embodiments, R₁May be a substituted or unsubstituted 3 to 10 membered heterocyclic group, such as a 3 to 8 membered monocyclic heterocyclic group, a 6 to 8 membered bridged, fused or spiro bicyclic heterocyclic group, or a 3 to 8 membered nitrogen containing heterocyclic group. In some embodiments, R₁May be an unsubstituted 3-to 10-membered heterocyclic group, such as a 3-to 8-membered monocyclic heterocyclic group, a 6-to 8-membered bridged, fused or spiro bicyclic heterocyclic group, or a 3-to 8-membered nitrogen-containing heterocyclic group. In some embodiments, R₁Can be used forIs substituted or unsubstituted C₆-C₁₀Aryl, such as phenyl or naphthyl. In some embodiments, R₁May be unsubstituted C₆-C₁₀Aryl, such as phenyl or naphthyl. In some embodiments, R₁May be a substituted or unsubstituted 5 to 10 membered heteroaryl group, for example a 5 membered heteroaryl group, a 6 membered heteroaryl group, a 10 membered heteroaryl group or a 5 to 10 membered heteroaryl group having one or two nitrogen atoms. In some embodiments, R₁May be an unsubstituted 5 to 10 membered heteroaryl group, such as a 5 membered heteroaryl group, a 6 membered heteroaryl group, a 10 membered heteroaryl group or a 5 to 10 membered heteroaryl group having one or two nitrogen atoms. In some embodiments, R₁May be L-Y, for example:

where ". x" denotes the point of attachment of the L-Y moiety to the rest of the molecule. In some embodiments, when R₁When L-Y can be mentioned, R_3A、R_3B、R_3C、R_3DAnd R_3EMay not be L-Y.

In some embodiments, R₂Can be hydrogen, deuterium, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₂-C₆Alkenyl, acyl or- (SO)₂)-C₁-C₆An alkyl group. In some embodiments, R₂May be hydrogen. In some embodiments, R₂May be deuterium. In some embodiments, R₂C which may be substituted or unsubstituted₁-C₆For example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (linear or branched) or hexyl (linearOr branched). In some embodiments, R₂May be unsubstituted C₁-C₆For example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (linear or branched) or hexyl (linear or branched). In some embodiments, R₂C which may be substituted or unsubstituted₂-C₆Alkenyl groups, such as methylene, vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, sec-butenyl, tert-butenyl, pentenyl (linear or branched) or hexenyl (linear or branched). In some embodiments, R₂May be unsubstituted C₂-C₆Alkenyl groups, such as methylene, vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, sec-butenyl, tert-butenyl, pentenyl (linear or branched) or hexenyl (linear or branched). In some embodiments, R₂May be acyl, e.g. C₁-C₆Alkylcarbonyl such as acetyl (ethan-1-one), propan-1-one or 3-methylbutan-1-one. In some embodiments, R₂Can be- (SO)₂)-C₁-C₆Alkyl radicals, e.g., - (SO)₂) -methyl, - (SO)₂) -ethyl, - (SO)₂) -n-propyl, - (SO)₂) -isopropyl, - (SO)₂) -n-butyl, - (SO)₂) -isobutyl, - (SO)₂) -sec-butyl, - (SO)₂) -tert-butyl, - (SO)₂) -pentyl (linear or branched) or- (SO)₂) -hexyl (linear or branched).

In some embodiments, n may be 1,2, or 3. In some embodiments, n may be 1 or 2. In some embodiments, n may be 1. In some embodiments, n may be 2.

In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EEach of which may be independently hydrogen, deuterium, hydroxy, halogen, nitro, substituted or unsubstituted amino, substituted or unsubstituted C₁-C₆Alkoxy, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₂-C₆Alkenyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted 3 to 10 membered heterocyclyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl or L-Y. In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EOne or more of which may be hydrogen. In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EOne or more of which may be deuterium. In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EOne or more of which may be hydroxyl. In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EOne or more of which may be halogen, for example fluorine, chlorine or bromine. In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EOne or more of which may be nitro. In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EOne or more of which may be substituted amino, e.g. (C)₁-C₆Alkyl) amino, (3-to 10-membered heterocyclyl) amino or (C)₆-C₁₀Aryl) amino. In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EOne or more of which may be unsubstituted amino. In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EOne or more of which may be substituted C₁-C₆Alkyl which is unsubstituted C₁-C₆Haloalkyl, for example halomethyl, haloethyl, halo-n-propyl, haloisopropyl, halo-n-butyl, haloisobutyl, halo-sec-butyl, halo-tert-butyl, halopentyl (linear or branched) or halohexyl (linear or branched). In some casesIn embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EMay be unsubstituted C₁-C₆A fluoroalkyl group. In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EMay be unsubstituted C₁-C₆A chloroalkyl group. In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EMay be unsubstituted C₁-C₆Haloalkyl groups including fluorine and chlorine. In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EOne or more of which may be substituted or unsubstituted C₁-C₆Alkoxy, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy (linear or branched) or hexoxy (linear or branched). In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EMay be unsubstituted C₁-C₆Alkoxy, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy (linear or branched) or hexoxy (linear or branched). In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EOne or more of which may be substituted or unsubstituted C₁-C₆Alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (linear or branched) or hexyl (linear or branched). In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EMay be unsubstituted C₁-C₆Alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (linear or branched) or hexyl (linear or branched). In some casesIn embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EOne or more of which may be substituted or unsubstituted C₂-C₆Alkenyl groups, such as methylene, vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, sec-butenyl, tert-butenyl, pentenyl (linear or branched) or hexenyl (linear or branched). In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EMay be unsubstituted C₂-C₆Alkenyl groups, such as methylene, vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, sec-butenyl, tert-butenyl, pentenyl (linear or branched) or hexenyl (linear or branched). In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EOne or more of which may be substituted or unsubstituted C₃-C₈Cycloalkyl radicals, e.g. C₃-C₈Monocyclic cycloalkyl or C₆-C₈Bridged, fused or spiro bicyclic cycloalkyl. In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EMay be unsubstituted C₃-C₈Cycloalkyl radicals, e.g. C₃-C₈Monocyclic cycloalkyl or C₆-C₈Bridged, fused or spiro bicyclocycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, octahydropentalene, decahydronaphthalene, bicyclo [4.2.0]Octane and bicyclo [3.1.1]Heptane. In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EOne or more of which may be a substituted or unsubstituted 3-to 10-membered heterocyclic group, such as a 3-to 8-membered monocyclic heterocyclic group, a 6-to 8-membered bridged, fused or spiro bicyclic heterocyclic group, or a 3-to 8-membered nitrogen-containing heterocyclic group. In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EOne or more of which may be unsubstituted 3 to 10 membered heterocyclyl, e.g. 3 to 8 membered monocyclic heterocyclyl,A 6-to 8-membered bridged, fused or spiro bicyclic heterocyclic group or a 3-to 8-membered nitrogen-containing heterocyclic group. In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EOne or more of which may be substituted or unsubstituted alkoxyalkyl, e.g. C as described herein₁-C₄Alkoxy and C as described herein₁-C₄An alkyl group. In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EMay be unsubstituted alkoxyalkyl, e.g. C as described herein₁-C₄Alkoxy and C as described herein₁-C₄Alkyl groups such as methoxymethyl, ethoxymethyl or ethoxypropyl. In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EOne or more of which may be substituted or unsubstituted cycloalkylalkyl, e.g. C₃-C₈Monocyclic cycloalkyl or C₆-C₈Bridged, fused or spiro bicyclic cycloalkyl and C₁-C₆Alkyl, as described herein. In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EOne or more of which may be unsubstituted cycloalkylalkyl, e.g. C₃-C₈Monocyclic cycloalkyl or C₆-C₈Bridged, fused or spiro bicyclic cycloalkyl and C₁-C₆An alkyl group, as described herein, such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, or cyclohexylethyl. In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EOne or more of which may be a substituted or unsubstituted heterocyclylalkyl group, e.g., a 3-to 8-membered monocyclic heterocyclyl group, a 6-to 8-membered bridged, fused, or spiro bicyclic heterocyclyl group, or a 3-to 8-membered nitrogen-containing heterocyclyl group and C₁-C₆Alkyl, as described herein. In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EOne or more of which may be unsubstituted heterocyclylalkyl, e.g. 3 to 8 memberedMonocyclic heterocyclic group, 6-to 8-membered bridged, fused or spiro bicyclic heterocyclic group, or 3-to 8-membered nitrogen-containing heterocyclic group and C₁-C₆Alkyl, as described herein, for example pyrrolidinylmethyl, piperidinyl methyl, piperazinyl methyl, or morpholinylmethyl. In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EOne or more of which may be substituted or unsubstituted aralkyl, e.g. C₆-C₁₀Aryl (e.g. phenyl or naphthyl) and C₁-C₆Alkyl, as described herein. In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EOne or more of which may be unsubstituted aralkyl, e.g. C₆-C₁₀Aryl (e.g. phenyl or naphthyl) and C₁-C₆Alkyl, as described herein, for example benzyl or phenethyl. In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EOne or more of which may be substituted or unsubstituted heteroaralkyl, e.g., 5-membered heteroaryl, 6-membered heteroaryl, 10-membered heteroaryl, or 5-to 10-membered heteroaryl having one or two nitrogen atoms and C₁-C₆Alkyl, as described herein. In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EOne or more of which may be unsubstituted heteroaralkyl, e.g., 5-membered heteroaryl, 6-membered heteroaryl, 10-membered heteroaryl, or 5-to 10-membered heteroaryl having one or two nitrogen atoms and C₁-C₆Alkyl, as described herein, for example pyridylmethyl, pyrimidinylmethyl, or imidazolylmethyl. In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EOne of these may be L-Y, for example:

where ". x" denotes the point of attachment of the L-Y moiety to the rest of the molecule.

In some embodiments, when R_3A、R_3B、R_3C、R_3DAnd R_3EWhen any one of them may be L-Y, R₁And cannot be L-Y. In some embodiments, R_3AAnd cannot be hydrogen. In some embodiments, R_3BAnd cannot be hydrogen. In some embodiments, R_3CAnd cannot be hydrogen. In some embodiments, R_3DAnd cannot be hydrogen. In some embodiments, R_3EAnd cannot be hydrogen.

In some embodiments, L may be-Z₁-(R₄)_t-Z₂–；–Z₁-(R₄-O-R₄)_t-Z₂–；–Z₁(R₄-NH-R₄)_t-Z₂–；–Z₁-(R₄-(NHCO)-R₄)_t-Z₂-; or-Z₁-(R₄-(CONH)-R₄)_t-Z₂-. In some embodiments, L may be-Z₁-(R₄-O-R₄)_t-Z₂-. In other embodiments, L may be-Z₁(R₄-NH-R₄)_t-Z₂-. In still other embodiments, L may be-Z₁-(R₄-(NHCO)-R₄)_t-Z₂-. In some embodiments, L may be Z₁-(R₄-(CONH)-R₄)_t-Z₂-. In other embodiments, L may be-Z₁-(R₄)_t-Z₂-. In still other embodiments, L may be-Z₁-(R₄-(NHC(O)NH)-R₄)_t-Z₂–。

In some embodiments, each R is₄C which may independently be unsubstituted₁-C₆Alkylene, for example methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, tert-butylene, pentylene (linear or branched) or hexylene (linear or branched). In some embodiments, each R is₄The groups are the same. In some embodiments, each R is₄The groups are different.

In some embodiments, t may be 1,2,3, 4,5, or 6. In some embodiments, t may be 1. In some embodiments, t may be 2. In some embodiments, t may be 3. In some embodiments, t may be 4. In some embodiments, t may be 5. In some embodiments, t may be 6.

Some embodiments of L are shown in table a below.

TABLE A

In some embodiments of table a, each R is₄May independently be C₁-C₄Alkylene, for example methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene or sec-butylene. In some embodiments of table a, each R is₄Is methylene. In some embodiments of table a, each R is₄Is an ethylene group. In some embodiments of table a, each R is₄Is n-propylene. In some embodiments of table a, each R is₄Is n-butylene. In some embodiments of table a, each R is₄May be the same. In some embodiments of table a, each R is₄May be different. For example, one R₄May be methylene and the other R₄May be an ethylene group; a R₄May be methylene and the other R₄May be n-propylene; a R₄May be methylene and the other R₄May be n-butylene; a R₄May be ethylene and the other R₄May be n-propylene; or a R₄May be ethylene and the other R₄May be n-butylene.

In some embodiments, Y may be

Wherein Y may be derivatized to link to L. As used herein, the phrase "Y derivatized to link to L" is used with ordinary skill in the artAs understood by the person using it. For example, when Y is derivatized to be attached to L, Y may be:

wherein denotes the point of attachment to the L group.

In some embodiments, Y is₁、Y₂、Y₃、Y₄And Y₅Is carbon (e.g. CR)_3A、CR_3B、CR_3C、CR_3DAnd/or CR_3E). In some embodiments, Y is₁、Y₂、Y₃、Y₄And Y₅Is carbon. In some embodiments, Y is₁、Y₂、Y₃、Y₄And Y₅Two of which are carbon. In some embodiments, Y is₁、Y₂、Y₃、Y₄And Y₅Three of which are carbon. In some embodiments, Y is₁、Y₂、Y₃、Y₄And Y₅Four of which are carbon. In some embodiments, Y is₁、Y₂、Y₃、Y₄And Y₅All five of which are carbon.

In some embodiments, when Q₁Is CH₂When then R is_3A、R_3B、R_3C、R_3DAnd R_3EOne or more of which cannot be hydrogen. In some embodiments, when Q₁When it is a bond, then R_3A、R_3B、R_3C、R_3DAnd R_3EOne or more of which cannot be hydrogen. In some embodiments, when R₁When L-Y is present, R_3A、R_3B、R_3C、R_3DAnd R_3ENone of which is L-Y. In some embodiments, when Q₁Is a bond, X₁Is hydrogen or methyl and Q₂Is CH₂When the current is over; then R is₁、R_3A、R_3B、R_3C、R_3DAnd R_3EOne of them is L-Y. In some embodiments, when Q₂When can be a bond, Q₁Can be a bond or CH₂。

In some embodiments, each R is₁May independently be halogen (e.g. fluorine, chlorine or bromine), substituted or unsubstituted amino (e.g. -NH)₂Dimethylamino, diethylamino, isopropylethylamino, phenylamino, or benzylamino), unsubstituted C₁-C₆Haloalkyl (e.g., -CF)₃、-CHF₂、-CH₂F、-CH₂CF₃or-CH₂CH₂CF₃) Substituted or unsubstituted C₁-C₆An alkoxy group (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy (linear or branched), or hexyloxy (linear or branched)) or a substituted or unsubstituted C₁-C₆Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (linear or branched), or hexyl (linear or branched)). In some embodiments, each R is₁May independently be halogen (e.g. fluorine, chlorine or bromine), unsubstituted amino, unsubstituted C₁-C₆Haloalkyl, unsubstituted C₁-C₆Alkoxy (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy (linear or branched), or hexoxy (linear or branched)) or unsubstituted C₁-C₆Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (linear or branched), or hexyl (linear or branched)).

In some embodiments, each R is₁Can independently be fluorine, chlorine, -NH₂、-NH(CH₃)、-N(CH₃)₂、-CF₃、-OCH₃、-OCH₂CH₃、-OCH(CH₃)₂、-CH₃、-CH₂CH₃or-CH (CH)₃)₂。

In some embodiments, ring B may be selected from:

in some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EEach of which may be independently hydrogen, deuterium, hydroxy, halogen (e.g., fluorine, chlorine or bromine), nitro, substituted or unsubstituted amino (e.g., -NH₂Dimethylamino, diethylamino, isopropylethylamino, phenylamino, or benzylamino), substituted or unsubstituted C₁-C₆An alkoxy group (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy (linear or branched), or hexyloxy (linear or branched)) or a substituted or unsubstituted C₁-C₆Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (linear or branched) or hexyl (linear or branched)), substituted or unsubstituted C₂-C₆Alkenyl (e.g., ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, secondary butenyl, tertiary butenyl, pentenyl (linear or branched) or hexenyl (linear or branched)), substituted or unsubstituted C₃-C₈Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl), substituted or unsubstituted 3-to 10-membered heterocyclyl (e.g., 3-to 8-membered monocyclic heterocyclyl containing one or two heteroatoms selected from oxygen and nitrogen, or 6-to 8-membered bicyclic heterocyclyl containing one or two heteroatoms selected from oxygen and nitrogen), substituted or unsubstituted alkoxyalkyl (e.g., methoxymethyl, ethoxyethyl, or methoxy-t-heterocyclyl)Butyl), substituted or unsubstituted cycloalkylalkyl (e.g., C)₃-C₈Cycloalkyl radicals, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, via C₁-C₃An alkyl group (e.g., methyl, ethyl, n-propyl, or isopropyl) attached to the remainder of the compound), a substituted or unsubstituted heterocyclylalkyl group (e.g., a 3-to 8-membered monocyclic heterocyclyl containing one or two heteroatoms selected from oxygen and nitrogen, via C)₁-C₃Alkyl groups (e.g. methyl, ethyl, n-propyl or isopropyl) attached to the remainder of the compound), substituted or unsubstituted aralkyl groups (e.g. phenyl or naphthyl, which are linked via C₁-C₃Alkyl groups (e.g. methyl, ethyl, n-propyl or isopropyl) attached to the remainder of the compound) or substituted or unsubstituted heteroaralkyl groups, e.g. five-, six-or ten-membered heteroaryl groups containing one oxygen, one nitrogen, one oxygen and one nitrogen, two nitrogens or three nitrogens, which is via C₁-C₃An alkyl group (e.g., methyl, ethyl, n-propyl, or isopropyl) is attached to the remainder of the compound).

In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EEach of which may independently be hydrogen, deuterium, hydroxy, halogen (e.g., fluoro, chloro or bromo), nitro, substituted or unsubstituted amino (e.g., -NH)₂Dimethylamino, diethylamino, isopropylethylamino, phenylamino, or benzylamino), unsubstituted C₁-C₆Haloalkyl (e.g., -CF)₃、–CHF₂、–CH₂F、–CH₂CF₃or-CH₂CH₂CF₃) Unsubstituted C₁-C₆Alkoxy (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy (linear or branched) or hexoxy (linear or branched)) or unsubstituted C₁-C₆Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (straight chain)Or branched) or hexyl (linear or branched)), unsubstituted C₂-C₆Alkenyl (e.g. ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, sec-butenyl, tert-butenyl, pentenyl (linear or branched) or hexenyl (linear or branched)), unsubstituted C₃-C₈Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl), unsubstituted 3 to 10 membered heterocyclyl (e.g., 3 to 8 membered monocyclic heterocyclyl containing one or two heteroatoms selected from oxygen and nitrogen, or 6 to 8 membered bicyclic heterocyclyl containing one or two heteroatoms selected from oxygen and nitrogen), unsubstituted alkoxyalkyl (e.g., methoxymethyl, ethoxyethyl, or methoxy-tert-butyl), unsubstituted cycloalkylalkyl (e.g., C)₃-C₈Cycloalkyl radicals, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, via C₁-C₃An alkyl group (e.g., methyl, ethyl, n-propyl, or isopropyl) attached to the remainder of the compound), an unsubstituted heterocyclylalkyl group (e.g., a 3-to 8-membered monocyclic heterocyclyl containing one or two heteroatoms selected from oxygen and nitrogen, via C)₁-C₃Alkyl groups (e.g. methyl, ethyl, n-propyl or isopropyl) attached to the remainder of the compound), unsubstituted aralkyl groups (e.g. phenyl or naphthyl, via C)₁-C₃An alkyl group (e.g., methyl, ethyl, n-propyl, or isopropyl) attached to the remainder of the compound) or unsubstituted heteroaralkyl (e.g., a five-, six-, or ten-membered heteroaryl group containing one oxygen, one nitrogen, one oxygen, and one nitrogen, two nitrogens, or three nitrogens, which is linked via C)₁-C₃An alkyl group (e.g., methyl, ethyl, n-propyl, or isopropyl) is attached to the remainder of the compound).

In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EEach of which may independently be hydrogen, halogen (e.g. fluorine, chlorine or bromine), unsubstituted C₁-C₆Haloalkyl (e.g., -CF)₃、–CHF₂、–CH₂F、–CH₂CF₃or-CH₂CH₂CF₃) Unsubstituted C₁-C₆Alkoxy (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy (linear or branched) or hexoxy (linear or branched)), unsubstituted C₁-C₆Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (linear or branched), or hexyl (linear or branched)), an unsubstituted 3 to 10-membered heterocyclyl group (e.g., a 3 to 8-membered monocyclic heterocyclyl group containing one or two heteroatoms selected from oxygen and nitrogen, or a 6 to 8-membered bicyclic heterocyclyl group containing one or two heteroatoms selected from oxygen and nitrogen) or an unsubstituted 3 to 10-membered heterocyclylalkyl group (e.g., a 3 to 8-membered monocyclic heterocyclyl group containing one or two heteroatoms selected from oxygen and nitrogen, or a 6 to 8-membered bicyclic heterocyclyl group containing one or two heteroatoms selected from oxygen and nitrogen, which is linked to the remainder of the compound by a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (linear or branched), or hexyl (linear or branched) group).

In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3ECan be halogen (e.g. fluorine, chlorine or bromine), unsubstituted C₁-C₆Haloalkyl, unsubstituted C₁-C₆Alkoxy (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy (linear or branched) or hexoxy (linear or branched)), unsubstituted C₁-C₆An alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (linear or branched), or hexyl (linear or branched)), an unsubstituted 3-to 10-membered heterocyclic group (e.g., a 3-to 8-membered monocyclic heterocyclic group containing one or two heteroatoms selected from oxygen and nitrogen, or a 6-to 8-membered bicyclic heterocyclic group containing one or two heteroatoms selected from oxygen and nitrogen), or an unsubstituted 3-to 10-membered heterocyclylalkylheterocyclic group(e.g., a 3-to 8-membered monocyclic heterocyclic group containing one or two heteroatoms selected from oxygen and nitrogen, or a 6-to 8-membered bicyclic heterocyclic group containing one or two heteroatoms selected from oxygen and nitrogen, which is linked to the remainder of the compound through a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (linear or branched), or hexyl (linear or branched) group), and R_3A、R_3B、R_3C、R_3DAnd R_3EThe others in (a) are hydrogen.

In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EOne of them may be fluorine, chlorine, -CF₃、-OCH₃Unsubstituted C₁-C₆Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (linear or branched) or hexyl (linear or branched)), unsubstituted 3 to 10 membered heterocyclyl (e.g., 3 to 8 membered monocyclic heterocyclyl containing one or two heteroatoms selected from oxygen and nitrogen, or 6 to 8 membered bicyclic heterocyclyl containing one or two heteroatoms selected from oxygen and nitrogen), or unsubstituted 3 to 10 membered heterocyclylalkyl (e.g., 3 to 8 membered monocyclic heterocyclyl containing one or two heteroatoms selected from oxygen and nitrogen, or 6 to 8 membered bicyclic heterocyclyl containing one or two heteroatoms selected from oxygen and nitrogen) linked to the rest of the compound through a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (linear or branched) or hexyl (linear or branched) group), and R is_3A、R_3B、R_3C、R_3DAnd R_3EThe others in (a) are hydrogen.

In some embodiments, R_3A、R_3B、R_3C、R_3DAnd R_3EOne of which may be selected from:

and R is_3A、R_3B、R_3C、R_3DAnd R_3EThe others of (a) may be hydrogen.

In some embodiments, L may be-Z₁-(R₄-O-R₄)_t-Z₂-. In some embodiments, L may be-Z₁(R₄-NH-R₄)_t-Z₂-. In some embodiments, L may be Z₁-(R₄-(NHCO)-R₄)_t-Z₂-. In some embodiments, L may be-Z₁-(R₄-(CONH)-R₄)_t-Z₂-. In other embodiments, L may be-Z₁-(R₄-(NHC(O)NH)-R₄)_t-Z₂-. In some embodiments of this paragraph, t is 1. In some embodiments of this paragraph, t is 2.

In some embodiments, Z₁May be-NH-. In some embodiments, Z₁May be-O-. In some embodiments, Z₁Can be-CH₂-. In some embodiments, Z₁May be-NH (CO) -. In some embodiments, Z₁Can be-CH₂NH-. In some embodiments, Z₁Can be-NHCH₂-. In some embodiments, Z₂May be-NH-. In some embodiments, Z₂May be-O-. In some embodiments, Z₂Can be-CH₂-. In some embodiments, Z₂May be-NH (CO) -. In some embodiments, Z₂May be- (CO) NH-. In some embodiments, Z₂Can be-CH₂NH-. In some embodiments, Z₂Can be used foris-NHCH₂-. In some embodiments of this paragraph, Z₁And Z₂The same is true. In some embodiments of this paragraph, Z₁And Z₂Different. In some embodiments of this paragraph, when Z is₁Can be-NH-or Z₂May be-NH-. In some embodiments of this paragraph, when Z is₁Can be-O-or-Z₂May be-O-. In some embodiments of this paragraph, when Z is₁Can be-CH₂When is, Z₂Can be-CH₂-. In some embodiments of this paragraph, when Z is₁May be-NH (CO) -, Z₂May be-NH (CO) -. In some embodiments of this paragraph, when Z is₁Can be-CH₂NH-is, Z₂Can be-CH₂NH-. In some embodiments of this paragraph, when Z is₁Can be-CH₂NH (CO) -, Z₂May be-NH-. In some embodiments of this paragraph, when Z is₁Can be-CH₂NH (CO) -, Z₂May be-O-. In some embodiments of this paragraph, when Z is₁Can be-CH₂NH (CO) -, Z₂Can be-CH₂-. In some embodiments of this paragraph, when Z is₁Can be-CH₂NH (CO) -, Z₂May be-NH (CO) -. In some embodiments of this paragraph, when Z is₁Can be-CH₂NH (CO) -, Z₂Can be-CH₂NH–。

In some embodiments, each R is₄C which may independently be unsubstituted₁-C₄Alkylene, for example methylene, ethylene, n-propylene, isopropylene, n-butylene, sec-butylene or tert-butylene. In some embodiments, each R is₄C which may independently be unsubstituted₁-C₂Alkylene, such as methylene or ethylene.

In some embodiments, the compound of formula (I) is selected from:

a pharmaceutically acceptable salt or of any of the foregoing.

Some embodiments of the compounds of general formula (I) are shown in table B below.

TABLE B

In some embodiments of table B, R₂May be hydrogen. In some embodiments of table B, R₂C which may be substituted or unsubstituted₁-C₆Alkyl radicals, e.g. methylEthyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (linear or branched) or hexyl (linear or branched). In some embodiments of table B, R₂May be unsubstituted C₁-C₆Alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (linear or branched) or hexyl (linear or branched). In some embodiments of table B, R₂May be an acyl group, for example- (C ═ O) -methyl, - (C ═ O) -ethyl, - (C ═ O) -n-propyl, - (C ═ O) -isopropyl, - (C ═ O) -n-butyl, - (C ═ O) -isobutyl, - (C ═ O) -sec-butyl, - (C ═ O) -tert-butyl, - (C ═ O) -pentyl (linear or branched) or- (C ═ O) -hexyl (linear or branched). In some embodiments of table B, R₂Can be- (SO)₂)-C₁-C₆Alkyl radicals, e.g., - (SO)₂) -methyl, - (SO)₂) -ethyl, - (SO)₂) -n-propyl, - (SO)₂) -isopropyl, - (SO)₂) -n-butyl, - (SO)₂) -isobutyl, - (SO)₂) -sec-butyl, - (SO)₂) -tert-butyl, - (SO)₂) -pentyl (linear or branched) or- (SO)₂) -hexyl (linear or branched).

In some embodiments, the compound of formula (I) is selected from:

in some embodiments of this paragraph, R₁May be fluorine. In some embodiments of this paragraph, R₁May be chlorine. In some embodiments of this paragraph, R₁May be a hydroxyl group. In some embodiments of this paragraph, R₁May be-NH₂. In some embodiments of this paragraph, R₁May be-CF₃、–CHF₂or-CH₂F. In some embodiments of this paragraph, R₁May be unsubstituted C₁-C₆Alkoxy, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy (linear or branched) or hexoxy (linear or branched). In some embodiments of this paragraph, R₁May be unsubstituted C₁-C₆Alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (linear or branched) or hexyl (linear or branched). In some embodiments of this paragraph, R₁May be unsubstituted C₃-C₈Cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. In some embodiments of this paragraph, R₁May be an unsubstituted 3 to 10 membered heterocyclic group such as a monocyclic heterocyclic group, a bridged heterocyclic group or a fused heterocyclic group, including groups such as pyrrolidine, piperidine, piperazine and morpholine. In some embodiments of this paragraph, R_3BMay be a hydroxyl group. In some embodiments of this paragraph, R_3BMay be fluorine. In some embodiments of this paragraph, R_3BMay be chlorine. In some embodiments of this paragraph, R_3BAmino which may be substituted or unsubstituted, e.g. -NH₂Dimethylamino, diethylamino, isopropylethylamino, phenylamino, or benzylamino. In some embodiments of this paragraph, R_3BMay be-CF₃、–CHF₂or-CH₂F. Some practice in this paragraphIn the embodiment, R_3BMay be unsubstituted C₁-C₆Alkoxy, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy (linear or branched) or hexoxy (linear or branched). In some embodiments of this paragraph, R_3BMay be unsubstituted C₁-C₆Alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (linear or branched) or hexyl (linear or branched). In some embodiments of this paragraph, R_3BMay be unsubstituted C₃-C₈Cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. In some embodiments of this paragraph, R_3CC which may be substituted or unsubstituted₃-C₈Cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. In some embodiments of this paragraph, R_3CMay be unsubstituted C₃-C₈Cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. In some embodiments of this paragraph, R_3CA 3 to 10 membered heterocyclic group which may be substituted or unsubstituted, such as a monocyclic heterocyclic group, a bridged heterocyclic group or a fused heterocyclic group, including groups such as pyrrolidine, piperidine, piperazine and morpholine. In some embodiments of this paragraph, R_3CMay be an unsubstituted 3 to 10 membered heterocyclic group such as a monocyclic heterocyclic group, a bridged heterocyclic group or a fused heterocyclic group, including groups such as pyrrolidine, piperidine, piperazine and morpholine. In some embodiments of this paragraph, R_3CA 5 to 10 membered heteroaryl group which may be substituted or unsubstituted, for example a 5 or 6 membered heteroaryl group containing at least one nitrogen, for example pyrrole, imidazole, oxazole, thiazole, pyridine or pyrimidine. In some embodiments of this paragraph, R_3CMay be an unsubstituted 5 to 10 membered heteroaryl group, for example a 5 or 6 membered heteroaryl group containing at least one nitrogen, for example pyrrole, imidazole, oxazole, thiazole, pyridine or pyrimidine.

The compounds of general formula (I) may be provided in the form of pharmaceutically acceptable salts, solvates or tautomers thereof.

Some embodiments provide a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable inactive ingredient. The pharmaceutical composition may be formulated for intravenous injection, subcutaneous injection, oral administration, buccal administration, inhalation, nasal administration, topical administration, transdermal administration, ocular administration, or otic administration. The pharmaceutical composition may be in the form of tablets, pills, capsules, liquids, inhalants, nasal spray solutions, suppositories, suspensions, gels, colloids, dispersions, solutions, emulsions, ointments, lotions, eye drops or ear drops.

In some embodiments, the pharmaceutical composition is formulated as a gel, salve, ointment, cream, emulsion, or paste for topical application to the skin.

Some embodiments provide a method of inhibiting the activity of a cytokine comprising contacting a cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Some embodiments provide methods of inhibiting aiolos activity comprising contacting a cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Some embodiments provide a method of inhibiting ikaros activity comprising contacting a cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the cell is a cancer cell.

Some embodiments provide methods of inhibiting hellios activity comprising contacting a cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the cell is a cancer cell.

Some embodiments provide methods of inhibiting CK-1 α activity comprising contacting a cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In some embodiments, inhibiting protein activity may comprise reducing protein activity by 20-50%, 30-70%, 40-90%, or any value in between. For example, inhibiting protein activity can include decreasing protein activity by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or any value in between.

Some embodiments provide a method of treating, ameliorating, or preventing a disease, disorder, or condition associated with a protein selected from the group consisting of cytokines, aiolos, ikaros, helioss, CK1 α, and a combination of any of the foregoing, in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In some embodiments, the cytokine is selected from the group consisting of IL-1 β, IL-2, IL-6, and TNF α in some embodiments, the individual is known to have wild-type IL-1 β, IL-2, IL-6, and TNF α in some embodiments, the individual is known to overexpress one or more of IL-1 β, IL-2, IL-6, and TNF α in some embodiments, the individual is known to have mutated forms of IL-1 β, IL-2, IL-6, and/or TNF α.

In some embodiments, the cytokine is TNF α in some embodiments, the individual is known to have wild-type TNF α in some embodiments, the individual is known to overexpress TNF α in some embodiments, the individual is known to have a mutant form of TNF α in some embodiments, the protein is aiolos in some embodiments, the individual is known to have a wild-type aiolos in some embodiments, the individual is known to overexpress aiolos in some embodiments, the individual is known to have a mutant form of aiolos in some embodiments, the protein is ikaros in some embodiments, the individual is known to have a wild-type ikaros in some embodiments, the individual is known to overexpress arik in some embodiments, the individual is known to have a mutant form of ikaros in some embodiments, the protein is known to have a hemis in some embodiments, the protein is known to have a mutant form of hepios in some embodiments, the wild-type hepios in some embodiments, the individual is known to have a mutant form of hepios in some embodiments, the mutant form of hepios 3, the individual is known to have no, some embodiments, the mutant form of hepios in some embodiments, the individual is known to have No. 3, the mutant form of hepios in some embodiments, the embodiment, the protein is known to have some embodiments, the mutant form of hepios.

Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description.

Definition of

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications mentioned herein are incorporated by reference in their entirety, unless otherwise indicated. Unless otherwise indicated, where there are multiple definitions for terms herein, the definition in this section controls. As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Unless otherwise specified, conventional mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacological methods are employed. Unless otherwise stated, the use of "or" and "means" and/or ". Furthermore, the use of the term "including" as well as other forms such as "includes", "includes" and "included" is not limited. As used in this specification, the terms "comprises(s)", and "comprising" should be interpreted as having an open-ended meaning, whether in transitional phrases or in the context of the claims. In other words, the term should be interpreted synonymously with the phrases "having at least" or "including at least". When used in the context of a method, the term "comprising" means that the method includes at least the recited steps, but may include additional steps. The term "comprising" when used in the context of a compound, composition or device means that the compound, composition or device includes at least the recited features or components/ingredients, but may also include additional external features or components/ingredients.

The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

The term "co-administration" and similar terms as used herein are broad terms and are to be given their ordinary and customary meaning to those of ordinary skill in the art (and are not to be limited to a specific or customized meaning) and refer to, but are not limited to, administration of a selected therapeutic agent to a single patient and are intended to encompass treatment regimens in which the agents are administered by the same or different routes of administration or at the same or different times.

The terms "effective amount" and "therapeutically effective amount" are broad terms and are to be given their ordinary and customary meaning to those of ordinary skill in the art (and are not to be limited to a specific or customized meaning) and refer to, but are not limited to, the administration of a sufficient amount of an agent or compound that will alleviate one or more symptoms of the disease or condition being treated to some extent. The result can be a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein that is required to provide a clinically significant reduction in disease symptoms. An appropriate "effective" amount in any individual case can be determined using techniques such as dose escalation studies. When a drug has been approved by the U.S. Food and Drug Administration (FDA) or corresponding foreign drug agency, a "therapeutically effective amount" optionally refers to a dose approved by the FDA or its corresponding foreign agency for the treatment of the identified disease or condition.

As herein describedAs used, any "R" group, such as but not limited to R₂、R₃、R₄、R₅、R₆、R₉And R₁₀And represents a substituent which may be attached to the indicated atom. The R group may be substituted or unsubstituted. If two "R" groups are described as "together," the R groups, together with the atoms to which they are attached, can form a cycloalkyl, aryl, heteroaryl, or heterocyclic ring. For example, without limitation, if R²And R³Or R is²、R³Or R⁴And the atoms to which they are attached are designated as "linked together" or "joined together," meaning that they are covalently bonded to each other to form a ring:

whenever a group is described as "substituted" or "optionally substituted," the group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as "unsubstituted or substituted," if substituted, the substituent may be selected from one or more of the specified substituents. If no substituent is specified, it is intended that the specified or "substituted" group may be individually and independently substituted with one or more groups individually and independently selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, (heterocyclyl) alkyl, hydroxy, protected hydroxy, alkoxy, aryloxy, acyl, cyano, halogen, ester, nitro, silyl, haloalkyl, haloalkoxy, unsubstituted amino, substituted amino, and protected derivatives thereof.

As used herein, "C" is_aTo C_b"(wherein" a "and" b "are integers) means the number of carbon atoms in an alkyl, alkenyl, or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, aryl, heteroaryl, or heterocyclyl group. That is, the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl ring may contain "a" through "b" (both inclusive)Carbon atoms. Thus, for example, "C₁To C₄Alkyl "or" C₁-C₄Alkyl "refers to all alkyl groups having 1 to 4 carbons, i.e., CH₃-、CH₃CH₂-、CH₃CH₂CH₂-、(CH₃)₂CH-、CH₃CH₂CH₂CH₂-、CH₃CH₂CH(CH₃) -and (CH)₃)₃C-. Likewise, for example, a heterocyclyl group can contain "a" through "b" (both inclusive) total atoms, e.g., a 3-to 10-membered heterocyclyl group, which includes 3 to ten total atoms (carbon and heteroatoms). If "a" and "b" are not specified with respect to alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, the broadest ranges described in these definitions are assumed.

As used herein, "alkyl" refers to a straight or branched hydrocarbon chain comprising a fully saturated (no double or triple bonds) hydrocarbon group. The alkyl group can have 1 to 20 carbon atoms (whenever appearing herein, a numerical range such as "1 to 20" refers to each integer in the given range; e.g., "1 to 20 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also encompasses occurrences of the term "alkyl" where no numerical range is specified). The alkyl group can also be a medium size alkyl group having 1 to 10 carbon atoms. The alkyl group may also be a lower alkyl group having 1 to 6 carbon atoms. The alkyl group in the compound may be designated as "C₁-C₄Alkyl "or similar names. By way of example only, "C₁-C₄Alkyl "indicates the presence of one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl. Alkyl groups may be substituted or unsubstituted.

As used herein, "alkenyl" refers to an alkyl group, as defined herein, that contains one or more double bonds in a straight or branched hydrocarbon chain. Alkenyl groups may be unsubstituted or substituted.

As used herein, "alkynyl" refers to an alkyl group, as defined herein, that contains one or more triple bonds in a straight or branched hydrocarbon chain. Alkynyl groups may be unsubstituted or substituted.

As used herein, "alkylene" is a straight or branched chain alkyl group that refers to a bond formed to connect molecular fragments through their terminal carbon atoms. Examples include, but are not limited to, methylene (-CH)₂-) ethylene (-CH₂CH₂-) propylene (-CH)₂CH₂CH2-) and butylene (-CH)₂CH₂CH₂CH₂-). Alkylene groups may be substituted by replacing one or more hydrogens of the alkylene group with substituents listed under the definition of "substituted".

As used herein, "cycloalkyl" refers to a fully saturated (no double or triple bonds) monocyclic or polycyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused manner. Cycloalkyl groups may contain 3 to 10 atoms in the ring or 3 to 8 atoms in the ring. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups may be unsubstituted or substituted.

As used herein, "cycloalkyl" refers to an all-carbocyclic system. Such systems may be unsaturated, may include some unsaturation, or may contain some aromatic moieties, or be fully aromatic. Cycloalkyl groups may contain 3 to 30 carbon atoms. Cycloalkyl groups may be unsubstituted or substituted.

As used herein, "cycloalkylalkyl" refers to a- (alkylene) -R group, wherein R is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropylmethyl and cyclohexylmethyl. Cycloalkylalkyl radicals may also be referred to as, for example, (C)₁-C₆Alkyl) -cycloalkyl. Cycloalkylalkyl groups may be unsubstituted or substituted.

As used herein, "aryl" refers to a carbocyclic (all-carbon) monocyclic or polycyclic aromatic ring system (including, e.g., fused, bridged, or spiro ring systems) having a fully delocalized pi-electron system throughout at least one of the ringsWherein two carbocycles share a chemical bond, e.g., one or more aryl rings and one or more aryl or non-aryl rings). The number of carbon atoms in the aryl group can vary. For example, aryl may be C₆-C₁₄Aryl radical, C₆-C₁₀Aryl or C₆And (4) an aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. The aryl group may be substituted or unsubstituted.

As used herein, "aralkyl" refers to a- (alkylene) -R group, wherein R is aryl as defined above. Examples include, but are not limited to, benzyl and phenethyl. Aralkyl may also be referred to as, for example, (C)₁-C₆Alkyl) -aryl. Aralkyl groups may be substituted or unsubstituted.

As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic ring system (having at least one ring containing a fully delocalized pi-electron system) containing one or more heteroatoms (i.e., elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur) and at least one aromatic ring. The number of atoms in the ring of the heteroaryl group can vary. For example, heteroaryl groups can contain 4 to 14 atoms in the ring, 5 to 10 atoms in the ring, or 5 to 6 atoms in the ring. Furthermore, the term "heteroaryl" includes fused ring systems in which two rings (such as at least one aryl ring and at least one heteroaryl ring or at least two heteroaryl rings) share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2, 3-oxadiazole, 1,2, 4-oxadiazole, thiazole, 1,2, 3-thiadiazole, 1,2, 4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. Heteroaryl groups may be substituted or unsubstituted.

As used herein, "heteroaralkyl" refers to a- (alkylene) -R group, wherein R is heteroaryl as defined above. Examples include, but are not limited to, picolinesAnd methyl pyrimidinyl. Heteroaralkyl radicals may also be referred to as, for example, (C)₁-C₆Alkyl) -heteroaryl. Heteroaralkyl groups may be substituted or unsubstituted.

As used herein, "heterocycle" or "heterocyclyl" refers to ternary, quaternary, five-membered, six-membered, seven-membered, eight-membered, nine-membered, ten-membered, up to 18-membered monocyclic, bicyclic, and tricyclic ring systems, wherein carbon atoms, together with 1 to 5 heteroatoms, form the ring system. The heterocyclic ring may optionally contain one or more unsaturated bonds, however, the unsaturated bonds are located in such a way that there are no completely delocalized pi-electron systems throughout all rings. The heteroatoms are independently selected from oxygen, sulfur and nitrogen. The heterocyclic ring may also contain one or more carbonyl or thiocarbonyl functional groups so that this definition includes oxo and thioxo systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused manner. In addition, any nitrogen in the heterocycle may be quaternized. Examples of such "heterocyclic" groups include, but are not limited to, 1, 3-dioxine, 1, 3-dioxane, 1, 4-dioxane, 1, 2-dioxolane, 1, 3-dioxolane, 1, 4-dioxolane, 1, 3-oxathiacyclohexane, 1, 4-oxathiadiene, 1, 3-oxathiacyclopentane, 1, 3-dithiolene, 1, 3-dithiolane, 1, 4-oxathiane, tetrahydro-1, 4-thiazine, 2H-1, 2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1, 3, 5-triazine, Imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, ethylene oxide, piperidine N-oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidinedione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiomorpholine sulfoxide, thiomorpholine sulfone, and benzo-fused analogs thereof (e.g., benzimidazolone, tetrahydroquinoline, and 3, 4-methylenedioxyphenyl). Heterocyclyl groups may be unsubstituted or substituted.

As used herein, "heterocyclylalkyl" refers to a- (alkylene) -R group, wherein R is a heterocyclyl as defined above. Examples include, but are not limited to, methylpyrrolidinyl and methylpiperidinyl. Heterocyclylalkyl radicals may also be referred to as, for example, (C)₁-C₆Alkyl) -heterocyclyl. Heterocyclylalkyl groups may be substituted or unsubstituted.

As used herein, "alkoxy" refers to the formula-OR, wherein R is alkyl as defined above. A non-limiting list of alkoxy groups is methoxy, ethoxy, n-propoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. Alkoxy groups may be substituted or unsubstituted.

As used herein, "alkoxyalkyl" refers to an alkyl group, as defined above, substituted with one or two alkoxy groups, as defined above. Examples include, but are not limited to, methoxyethyl, ethoxyethyl, and methoxypropyl. Alkoxyalkyl groups may be substituted or unsubstituted.

As used herein, "acyl" refers to hydrogen, alkyl, alkenyl, alkynyl or aryl as defined above as a substituent attached via a carbonyl as defined herein. Examples include formyl, acetyl, benzoyl and acryloyl, the preferred acyl group being C₁-C₆An alkylcarbonyl group. The acyl group may be substituted or unsubstituted.

As used herein, "hydroxyalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a hydroxyl group. Exemplary hydroxyalkyl groups include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and 2, 2-dihydroxyethyl. Hydroxyalkyl groups may be substituted or unsubstituted.

As used herein, "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced with a halogen (e.g., monohaloalkyl, dihaloalkyl, and trihaloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and 1-chloro-2-fluoromethyl, 2-fluoroisobutyl. Haloalkyl groups may be substituted or unsubstituted.

As used herein, "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced with a halogen (e.g., monohaloalkoxy, dihaloalkoxy, and trihaloalkoxy). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 1-chloro-2-fluoromethoxy, 2-fluoroisobutoxy. Haloalkoxy groups may be substituted or unsubstituted.

As used herein, "aryloxy" refers to — OR, wherein R is aryl as defined above, such as (but not limited to) phenyl. The aryloxy group may be substituted or unsubstituted.

The term "ester" refers to a "-C (═ O) OR" group, where R can be, for example, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, OR cycloalkyl. The esters may be substituted or unsubstituted.

As used herein, the term "unsubstituted amino" refers to-NH₂A group.

As used herein, the term "substituted amino" refers to-NR_aR_bGroup, wherein R_aAnd R_bIndependently selected from hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, aralkyl, heteroaralkyl, cycloalkylalkyl and heterocyclylalkyl groups as defined herein; and wherein R_aAnd R_bNo more than one of which may be hydrogen.

As used herein, the term "hydroxy" refers to an-OH group.

"cyano" refers to the "-CN" group.

"carbonyl" refers to a C ═ O group.

The term "halogen atom" or "halogen" as used herein means any one of the radio-stable atoms in column 7 of the periodic table of elements, such as fluorine, chlorine, bromine and iodine.

In all definitions set forth herein, the terms used to define the new terms are as previously defined herein.

In the case where the number of substituents is not specified (e.g., haloalkyl), one or more substituents may be present. For example, "haloalkyl" may include one or more of the same or different halogens. As another exampleExample, "C₁-C₃Alkoxyphenyl "may include one or more of the same or different alkoxy groups containing one, two or three atoms.

As used herein, abbreviations for any protecting group, amino acid and other compounds are in accordance with their common usage, accepted abbreviations or the IUPAC-IUB Commission on Biochem.11:942-944(1972)) unless otherwise indicated.

The terms "protecting group" and "protecting group" as used herein refer to any atom or group of atoms added to a molecule to prevent an existing group in the molecule from undergoing unwanted chemical reactions. Examples of protecting group moieties are described in t.w.greene and p.g.m.wuts, Protective Groups in Organic Synthesis, 3 rd edition john wiley & Sons, 1999; and j.f.w.mcomie, Protective Groups in Organic Chemistry plenum, 1973, both of which are incorporated herein by reference for the limited purpose of disclosing suitable protecting Groups. The protecting group moiety may be selected in such a way that it is stable to certain reaction conditions and is readily removed at a convenient stage using methodology known in the art. A non-limiting list of protecting groups includes benzyl; a substituted benzyl group; alkylcarbonyl (e.g., tert-Butoxycarbonyl (BOC), acetyl, or isobutyryl); an arylalkyl carbonyl group (e.g., benzyloxycarbonyl or benzoyl); substituted methyl ethers (e.g., methoxymethyl ether); substituted ethyl ethers; substituted benzyl ethers; tetrahydropyranyl ether; silyl ethers (e.g., trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl); esters (e.g., benzoates); carbonates (e.g., methoxymethyl carbonate); sulfonates (e.g., tosylate or mesylate); acyclic ketals (e.g., dimethyl acetal); cyclic ketals (e.g., 1, 3-dioxane or 1, 3-dioxolane); an acyclic acetal; a cyclic acetal; an acyclic hemiacetal; a cyclic hemiacetal; cyclic dithioketals (e.g., 1, 3-dithiane or 1, 3-dithiolane); and triarylmethyl groups (e.g., trityl; monomethoxytrityl (MMTr); 4,4 '-dimethoxytrityl (DMTr); or 4,4' -trimethoxytrityl (TMTr)).

As used herein, "leaving group" refers to any atom or moiety that is capable of being substituted by another atom or moiety in a chemical reaction. More specifically, in some embodiments, a "leaving group" refers to an atom or moiety that is substituted in a nucleophilic substitution reaction. In some embodiments, a "leaving group" is any atom or moiety that is the conjugate base of a strong acid. Examples of suitable leaving groups include, but are not limited to, tosylate and halogen. Non-limiting characteristics and examples of leaving groups can be found in, for example, Organic Chemistry, second edition, Francis Carey (1992), pp 328-331; introductions to Organic Chemistry, second edition, Andrew Streittwieser and Clayton HeathCock (1981), pp.169-171; and Organic Chemistry, fifth edition, John McMurry (2000), pages 398 and 408; for the limited purpose of disclosing features and examples of leaving groups, they are all incorporated herein by reference.

The term "pharmaceutically acceptable salt" as used herein is a broad term and is to be given its ordinary and customary meaning to those of ordinary skill in the art (and is not to be limited to a specific or customized meaning) and refers to, but is not limited to, salts of compounds that do not cause significant irritation to the organism to which they are administered and do not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutically acceptable salts can be obtained by reacting the compounds with inorganic acids, such as hydrohalic acids (e.g., HCl or HBr), H₂SO₄、HNO₃And H₃PO₄. Pharmaceutically acceptable salts can also be obtained by reacting a compound with an organic acid, such as an aliphatic or aromatic carboxylic or sulfonic acid, for example formic acid, AcOH, propionic acid, glycolic acid, pyruvic acid, malonic acid, maleic acid, fumaric acid, trifluoroacetic acid, benzoic acid, cinnamic acid, mandelic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, hexadiene diacid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid or naphthalenesulfonic acid. Pharmaceutically acceptable salts can also be obtained by reacting a compound with a base to form a salt, such as an ammonium salt; alkali metal salts such as Li salts, Na salts or K salts; alkaline earth metal salts, such as Ca salts, Mg salts; or an Al salt; salts of organic bases, e.g. dicyclohexylamine, N-methyl-D-reduced glucamine, tris (hydroxymethyl) methylamine, C₁-C₇Alkylamines, cyclohexylamine, dicyclohexylamine, triethanolamine, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, tromethamine and salts with amino acids (e.g. arginine and lysine); or salts with inorganic bases, e.g. Al (OH)₃、Ca(OH)₂、KOH、Na₂CO₃NaOH, etc.

Some embodiments provide pharmaceutically acceptable salts of formula (II). In some embodiments, the salt is selected from the group consisting of hydrochloride, sulfate, hemisulfate, acetate, fumarate, malate, and citrate.

The term "solvate" as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not limited to a special or customized meaning) and refers to, but is not limited to, a solvent complexed with a compound in a reproducible molar ratio, including, but not limited to, 0.5:1, 1:1, or 2: 1. Thus, the term "pharmaceutically acceptable solvate" refers to a solvate, wherein the solvent is one that does not cause significant irritation to the organism to which it is administered and does not abrogate the biological activity of the compound.

Some embodiments provide solvates of formula (I). In some embodiments, the solvent in the solvate is selected from water, ethanol, and acetone or combinations thereof.

It is to be understood that in any compound described herein having one or more chiral centers, each center can independently have the R configuration or the S configuration or mixtures thereof if absolute stereochemistry is not explicitly specified. Thus, the compounds provided herein can be enantiomerically pure, enantiomerically enriched, or can be stereoisomeric mixtures and include all diastereomeric and enantiomeric forms. Additionally, it is to be understood that in any of the compounds described herein having one or more double bonds that result in geometric isomers that can be defined as E or Z, each double bond can independently be E or Z or a mixture thereof. If desired, the stereoisomers are obtained by methods such as stereoselective synthesis and/or separation of stereoisomers by chiral chromatography columns. Likewise, it is to be understood that in any compound described, all tautomeric forms are also intended to be included.

Unless otherwise specified, whenever a substituent is depicted as a diradical (i.e., having two points of attachment to the rest of the molecule), it is understood that the substituent may be attached in any directed configuration. Thus, for example, depicted as-AE-or

Includes the case where the substituents are oriented such that a is attached at the leftmost attachment point of the molecule and a is attached at the rightmost attachment point of the molecule.

It is understood that when a compound disclosed herein has an unfilled valence, then the valence is intended to be filled with hydrogen and/or deuterium.

It is to be understood that the compounds described herein may be isotopically labeled or labeled by another other method including, but not limited to, the use of a chromophore or fluorescent moiety, a bioluminescent label, or a chemiluminescent label. Substitution with isotopes such as deuterium can afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Each chemical element present in the structure of the compound may include any isotope of that element. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood as being present in the compound. At any position of the compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen including, but not limited to, hydrogen-1 (protium), hydrogen-2 (deuterium), and hydrogen-3 (tritium). Thus, unless the context clearly indicates otherwise, a reference herein to a compound encompasses all possible isotopic forms.

It is understood that the methods and formulations described herein include the use of the salts, solvates, hydrates, and conformers of the compounds of the preferred embodiments, as well as metabolites and active metabolites of these compounds having the same type of activity. Conformers are structures that are conformationally isomeric. Conformational isomerism is the phenomenon in which molecules have the same structural formula but the conformation of the atoms around the rotating bond (conformers) is different. In certain embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents (such as water, ethanol, and the like). In other embodiments, the compounds described herein exist in unsolvated forms. Solvates contain either stoichiometric or non-stoichiometric amounts of solvent and may be formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein. The compounds of formula (I) may also be provided in, for example, amorphous form, milled form and nanoparticle form.

Likewise, it is to be understood that a compound described herein, e.g., a compound of the preferred embodiments, includes any form of the compound described herein (e.g., pharmaceutically acceptable salts, crystalline forms, amorphous forms, solvated forms, enantiomeric forms, tautomeric forms, and the like).

Dosing regimens

In some embodiments, about 1mg to about 5g of a compound of formula (I) is administered per day. In some embodiments, about 2mg to about 2g of a compound of formula (I) is administered per day. In some embodiments, the amount of the compound of formula (I) administered per day is or about 5mg to 1 g; 10mg to 800 mg; 20mg to 600 mg; 30mg to 400 mg; 40mg to 200 mg; 50mg to 100 mg; or any amount in between.

In some embodiments, about 1mg to about 5g of a compound of formula (I) is administered weekly. In some embodiments, about 2mg to about 2g of a compound of formula (I) is administered weekly. In some embodiments, the amount of the compound of formula (I) administered weekly is or about 5mg to 1 g; 10mg to 800 mg; 20mg to 600 mg; 30mg to 400 mg; 40mg to 200 mg; 50mg to 100 mg; or any amount in between.

In some embodiments, about 1mg to about 5g of a compound of formula (I) is administered per treatment cycle. In some embodiments, about 2mg to about 2g of a compound of formula (I) is administered per treatment cycle. In some embodiments, the amount of the compound of formula (I) administered per treatment cycle is or is from about 5mg to about 1 g; 10mg to 800 mg; 20mg to 600 mg; 30mg to 400 mg; 40mg to 200 mg; 50mg to 100 mg; or any amount therebetween.

In some embodiments, at least once per day; twice a day; three times a day; or four times daily administration of a compound of formula (I). In some embodiments, at least once per week; twice a week; three times per week; or four times a week. In some embodiments, each treatment cycle lasts for 1 day; 2 days; 3 days; 4 days; 5 days; 6 days; 7 days; 8 days; 9 days; 10 days; 11 days; 12 days; 13 days; 14 days, or any time in between. In some embodiments, each treatment cycle has at least 1 day between administrations of the compound of formula (I); 2 days; 3 days; 4 days; 5 days; 6 days; 7 days; 8 days; 9 days; 10 days; 11 days; 12 days; 13 days; or 14 days.

In some embodiments, the compound of formula (I) is provided intravenously in about 10min, about 20min, about 30min, about 1h, about 1.5h, about 2h, about 2.5h, about 3h, about 3.5h, about 4h, or any time therebetween.

Examples

Further embodiments are disclosed in further detail in the following examples, which are not intended to limit the scope of the claims in any way.

The compounds disclosed herein were characterized using Bruker AV-500 and DRX-500NMR spectrometers and a Perkin Elmer PE-SCIEX API-150 mass spectrometer.

In the synthetic procedures described herein, "work-up and purification" means that after extraction of the aqueous phase the organic layers are combined, washed with brine, washed with Na₂SO₄Drying, filtering, concentrating, and using the specified solvent systemThe product was purified by silica gel chromatography. Work-up and purification may also include 10% Na before washing with brine₂S₂O₃Aqueous solution/saturated NaHCO₃The aqueous solution (1:1) is subjected to an optional washing step.

Example 1

Compound 1: (S) -3- (4- ((4- (morpholinylmethyl) benzyl) oxy) -1-oxoisoindolin-2-yl) azepine Cycloheptane-2, 7-diones

To a solution of 4- (diethoxymethyl) benzaldehyde (2.43g,11.67mmol) in MeOH (40mL) at 0 deg.C was added NaBH₄(886.7mg,23.34 mmol). The suspension was stirred at RT for 3 h. The solvent was then removed, the residue diluted with water and extracted with DCM. The combined organic layers were washed with Na₂SO₄Drying, filtration, concentration and purification of the residue by silica gel chromatography with EtOAc/petroleum ether (10% to 23%) gave (4- (diethoxymethyl) phenyl) methanol 1.1 as a colourless oil (2.21g, 90% yield). MS (ESI) M/z 165.1[ M-42 ]]⁺.

To a solution of compound 1.2(323mg,1.24mmol) in THF (20mL) at 0 deg.C was added 1.1(326.5mg,1.55mmol) followed by PPh₃(650.4mg,2.48 mmol). A solution of DEAD (431.9mg,2.48mmol) in THF (1mL) was added dropwise and the suspension was stirred at RT for 16 h. The solvent was removed and the residue was purified by silica gel chromatography using EtOAc/petroleum ether (40% to 100%) to give compound 1.3 as a white solid (373mg, 66.7% yield). MS (ESI) M/z407.1[ M-45 ]]⁺.

To a solution of compound 1.3(473mg,1.05mmol) in THF (10mL) at RT was added 4M HCl (1.31mL) and the reaction was stirred at RT for 30 min. The solvent was removed and the residue was dried under vacuum to give compound 1.4 as a white solid (397mg, 100% yield). MS (ESI) M/z 379.1[ M +1 ]]⁺.

To a solution of compound 1.4(396.9mg,1.05mmol) in fluorobenzene/DMSO (30mL/5mL with 1 drop in DMSO) was added Dess-Martin reagent (1.12g,2.63 mmol). Heating the suspension at 80 deg.C to 18h. Additional Dess-Martin reagent (550mg) was added and the mixture was heated at 80 ℃ for 5 h. The mixture was cooled to RT and filtered. The filtrate was added to saturated Na₂S₂O₃In aqueous solution. The suspension was stirred at 0 ℃ for 5min and then extracted with DCM. Work-up and purification by silica gel chromatography using EtOAc/petroleum ether (40-100%) afforded compound 1.5(184mg, 45% yield) as a white solid. MS (ESI) M/z 393.1[ M +1 ]]⁺.

To a solution of Compound 1.5(76mg,0.194mmol) in DCM (10mL) was added morpholine (25.3mg,0.291mmol), followed by NaBH (OAc)₃(82.3mg,0.384 mmol). The mixture was stirred at RT for 48H, concentrated, purified by prep-TLC using EtOAc, then further purified by prep-HPLC (5 μ M C18 column, 0.1% TFA in H)₂O solution, 0.1% TFA in ACN, 5% -95% 0.1% TFA in ACN) to give compound 1 as a white solid (30.7mg, 21.7% yield).¹H NMR(DMSO-d₆,400MHz)δ：10.70(s,1H),7.49-7.45(m,3H),7.35-7.31(m,4H),5.24-5.21(m,3H),4.47(s,2H),3.57(s,4H),3.47(s,2H),3.08(t,J＝11.2Hz,1H),2.59-2.54(m,1H),2.35(s,5H),2.12-1.97(m,2H),1.86-1.74(m,1H).MS(ESI)m/z464.1[M+H]⁺.

Example 2

Compound 2: (S) -3- (4- ((4- ((2, 3-dihydro-4H-benzo [ b)][1,4]Oxazin-4-yl) methyl) benzyl) oxy 1-oxoisoindolin-2-yl) azepane-2, 7-dione

To a solution of compound 1.5(90mg,0.229mmol) in AcOH (4mL) at RT was added 3, 4-dihydro-2H-benzo [ b ] b][1,4]Oxazine (46.5mg,0.344mmol), followed by addition of NaBH (OAc)₃(145.6mg,0.687 mmol). The mixture was stirred at RT for 3h, the solvent was removed, and the residue was purified by prep-TLC with EtOAc/petroleum ether (1:2) and then further purified by prep-HPLC as described previously to give compound 2 as a white solid (45.0mg, 39% yield).¹H NMR(DMSO-d₆,400MHz)δ：10.69(s,1H),7.49-7.45(m,3H),7.35-7.31(m,4H),6.70-6.63(m,3H),6.51(t,J＝7.2Hz,1H),5.23-5.19(m,3H),4.47(d,J＝8.8Hz,4H),4.21(t,J＝3.6Hz,2H),3.39-3.35(m,2H),3.06(t,J＝13.2Hz,1H),2.57(d,J＝18.0Hz,1H),2.36-2.29(m,1H),2.09-1.99(m,2H),1.85-1.74(m,1H).MS(ESI)m/z 512.2[M+H]⁺.

Example 3

Compound 3: ((S) -3- (4- ((3-chloro-4- (morpholinylmethyl) benzyl) oxy) -1-oxoisoindoline-2-) Yl) azepane-2, 7-dione

To a solution of methyl 3-chloro-4-formylbenzoate (500mg,2.52mmol) in methanol (10mL) at RT was added 2, 2-dimethoxypropane (393.6mg,3.78mmol) followed by p-TsOH (48mg,0.252 mmol). The mixture was refluxed for 16h, the solvent was removed, and the residue was diluted with EtOAc (10mL) and saturated NaHCO₃Washing with aqueous solution over Na₂SO₄Dried, filtered and concentrated to give methyl 3-chloro-4- (dimethoxymethyl) benzoate as a yellow oil (540mg, 87.8% yield).¹HNMR(DMSO-d₆,300MHz)δ7.94(s,2H),7.71(d,J＝8.4Hz,1H),5.60(s,1H),3.87(s,3H),3.31(d,J＝0.9Hz,6H).

To a solution of methyl 3-chloro-4- (dimethoxymethyl) benzoate (480mg,2.05mmol) in THF (20mL) at 0 deg.C was added LiAlH₄(3.074mL,1M in THF). The suspension was stirred at RT for 2 h. Water (1mL) was added slowly to the reaction, followed by 10% NaOH (2mL), and then water (1 mL). The suspension was filtered and the filtrate was extracted with EtOAc. The combined organic layers were washed with Na₂SO₄Dried, filtered and concentrated to give crude (3-chloro-4- (dimethoxymethyl) phenyl) methanol 3.1(380mg) as a yellow oil, which was used directly in the next step without further purification.¹H NMR(CDCl₃,300MHz)δ7.60(d,J＝8.1Hz,1H),7.39(s,1H),7.26(d,J＝7.2Hz,1H),5.63(s,1H),4.67(s,2H),3.38(d,J＝0.9Hz,6H).

To compound 3.1(264mg,1.22mmol) in THF (15mL) at 0 deg.C) To the solution was added compound 3.2(260mg,1.0mmol) followed by PPh₃(524.6mg,2.0 mmol). A solution of DEAD (348.3mg,2.0mmol) in THF (1mL) was added dropwise and the suspension was stirred at RT for 16 h. The solvent was removed and the residue was purified by silica gel chromatography with EtOAc/petroleum ether (40% to 100%) to give compound 3.3 as a white solid (262mg, 39% yield). MS (ESI) M/z427.1[ M-31 ]]⁺.

To a solution of compound 3.3(262mg,0.572mmol) in THF (10mL) at RT was added 4M HCl (0.72 mL). The reaction was stirred at RT for 1 hour. The solvent was removed and the residue was dried under vacuum to give compound 3.4 as a white solid (235.7mg, 100% yield). MS (ESI) M/z 413.0[ M +1 ]]⁺.

To a solution of compound 3.4(235.7mg,0.572mmol) in fluorobenzene/DMSO (30mL/5mL, DMSO with 1 drop of water) was added Dess-Martin reagent (607mg,1.43 mmol). The suspension was heated at 80 ℃ for 18h and then cooled to RT. Additional Dess-Martin reagent (303mg) was added and the mixture was heated at 80 ℃ for 5h and then cooled to RT. The suspension was filtered and the filtrate was added to saturated Na₂S₂O₃Aqueous solution (30 mL). The suspension was stirred at 0 ℃ for 5min and then extracted with DCM. Work-up and purification by silica gel chromatography using EtOAc/petroleum ether (20% to 80%) afforded compound 3.5(72mg, 30% yield) as a white solid. MS (ESI) M/z 427.0[ M +1 ]]⁺.

To a solution of compound 3.5(54mg,0.127mmol) in DCM (5mL) at RT was added morpholine (22.1mg,0.254mmol) followed by NaBH (OAc)₃(80.8mg,0.38 mmol). The mixture was stirred at RT for 24 h. The solvent was removed and the residue was purified by preparative TLC using EtOAc/petroleum ether (2:1) and then by preparative HPLC as described previously to give compound 3 as a white solid (19.9mg, 32% yield).¹H NMR(DMSO-d₆,400MHz)δ：10.70(s,1H),7.57(s,1H),7.53-7.45(m,3H),7.33(t,J＝6.8Hz,2H),5.27(s,2H),5.20(d,J＝5.2Hz,1H),4.49(s,2H),3.59-3.56(m,6H),3.11-3.03(m,1H),2.58(d,J＝17.2Hz,1H),2.42(s,4H),2.38-2.33(m,1H),2.14-1.99(m,2H),1.86-1.76(m,1H).MS(ESI)m/z 498.1[M+H]⁺.

Example 4

Compound 4: (S) -3- (4- { [ p- (4-piperidinyl) phenyl]Methoxy } -2-isoindolinyl) -2, 7-aza Cycloheptanediones

To a solution of ethyl 4-iodobenzoate (750mg,2.72mmol), 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (923mg,2.99mmol) in DMF (50mL) at RT was added [1,1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride (400mg) and K₂CO₃(1.12g,8.16 mmol). The suspension was stirred at 85 ℃ for 16 hours. The mixture was filtered through a pad of celite. The filtrate was diluted with water and extracted with EtOAc. Work-up and purification with Petroleum ether/EtOAc (8: 1) afforded 4-tert-butyl-4 '-ethyl-1, 2,3, 6-tetrahydro- [1,1' -biphenyl]4,4' -dicarboxylic acid ester (720mg, 80% yield) as a white solid.

To a solution of 4-tert-butyl 4' -

ethyl

1,2,3, 6-tetrahydro- [1,1' -biphenyl ] -4,4' -dicarboxylate (720mg,2.18mmol) in EtOH (20mL) at RT was added palladium on charcoal (80 mg). The mixture was stirred at RT for 3 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated to give the crude product which was purified by silica gel chromatography eluting with petroleum ether/EtOAc (7: 1) to give ethyl 4- (4- (tert-butoxycarbonyl) cyclohexyl) benzoate (680mg, 93% yield) as a colorless oil.

LAH (1.0M in THF, 1.63mL,4.08mmol) was added dropwise to a solution of ethyl 4- (4- (tert-butoxycarbonyl) cyclohexyl) benzoate (680mg,2.04mmol) in THF (15mL) at 0 deg.C. The mixture was stirred at RT for 2 hours. With Na₂SO₄The reaction was quenched with decahydrate (5.0 g). After stirring at RT for 1 hour, the mixture was filtered, concentrated and purified by silica gel chromatography eluting with MeOH/DCM (3%) to give tert-butyl 4- (4- (hydroxymethyl) phenyl) piperidine-1-carboxylate (410mg, 69% yield) as a white solid.

To tert-butyl 4- (4- (hydroxymethyl) phenyl) piperidine-1-carboxylate (186mg,0.64mmol), (S) -4-hydroxy-2- (2-oxoazepane at 0 deg.CTo a solution of alk-3-yl) isoindolin-1-one (200mg,0.51mmol) and triphenylphosphine (524mg,1.024mmol) in THF (10mL) was added DEAD (178mg,1.024mmol) dropwise. The mixture was stirred at RT for 16H, then concentrated to give the crude product, which was purified by preparative-HPLC (5 μ M C18 column, H with 0.1% TFA)₂O solution, 0.1% TFA in ACN, 5% -95% 0.1% TFA in ACN) to afford tert-butyl (S) -4- (4- (((1-oxo-2- (2-oxoazepan-3-yl) isoindolin-4-yl) oxy) methyl) phenyl) piperidine-1-carboxylate (200mg, 56% yield) as a white solid. MS (ESI) M/z 478.1[ M + H-^tBu]⁺.

To a solution of tert-butyl (S) -4- (4- (((1-oxo-2- (2-oxoazepan-3-yl) isoindolin-4-yl) oxy) methyl) phenyl) piperidine-1-carboxylate (200mg,0.375mmol) in fluorobenzene/DMSO (10mL/1mL, DMSO containing 1 drop of water) at RT was added Dess-Martin reagent (397mg,0.94 mmol). The mixture was heated to 80 ℃ for 18 hours. The mixture was then cooled to 0 ℃ and quenched with saturated aqueous sodium thiosulfate (25 mL). After stirring at 0 ℃ for 15min, the mixture was extracted with DCM. Work-up and purification with EtOAc/petroleum ether (20% to 80%) afforded (S) -tert-butyl 4- (4- (((2- (2, 7-dioxoazepan-3-yl) -1-oxoisoindolin-4-yl) oxy) methyl) phenyl) piperidine-1-carboxylate (32mg, 15% yield) as a white solid.

To a solution of tert-butyl (S) -4- (4- (((2- (2, 7-dioxoazepan-3-yl) -1-oxoisoindolin-4-yl) oxy) methyl) phenyl) piperidine-1-carboxylate (110mg,0.2mmol) in DCM (4mL) was added TFA (1 mL). The mixture was stirred at RT for 2h, then saturated NaHCO was added₃The solution was brought to pH 7 and the mixture was extracted with DCM. The combined organic phases were passed over anhydrous Na₂SO₄Drying, filtration and concentration gave the crude product, which was purified by prep-HPLC as previously described to give compound 4 as a white solid (2.5mg, 6.2% yield).¹H NMR(DMSO-d₆,400MHz)δ：10.71(s,1H),8.64(s,1H),8.40(s,1H),7.49(m,3H),7.31(m,4H),5.23(m,3H),3.12(s,2H),2.85(m,2H),2.55(m,3H),2.32(m,1H),2.12(m,4H),2.07(m,3H).MS(ESI)m/z 448.0[M+H]⁺.

Example 5

Compound 5: (S) -3- (4- { [ p- (aminomethyl) phenyl]Methoxy } -2-isoindolinyl) -2, 7-aza Cycloheptanedione trifluoroacetic acid

To a solution of tert-butyl (3- (4- ((4- ((3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenoxy) propyl) carbamate (120mg,0.205mmol) in DCM (8mL) at RT was added TFA (2 mL). The mixture was stirred for 2 hours. The solvent was evaporated to give 3- ((2- ((4- (3-aminopropoxy) phenyl) amino) -5-methylpyrimidin-4-yl) amino) -N- (tert-butyl) benzenesulfonamide (102mg, crude) which was used directly in the next step without further purification. MS (ESI) M/z 485.1[ M + H ]]⁺.

To a solution of (S) -4-hydroxy-2- (2-oxoazepan-3-yl) isoindolin-1-one (700mg,2.69mmol), tert-butyl 4- (hydroxymethyl) benzylcarbamate (804mg,3.37mmol) and triphenylphosphine (1.41g,5.38mmol) in THF (10mL) at RT was added a solution of DEAD (938.7mg,5.38mmol) in THF (1 mL). The mixture was stirred at RT for 16 h. The solvent was evaporated and the residue was purified by silica gel chromatography, eluting with MeOH/DCM (0% to 7%) to give tert-butyl (S) -4- (((1-oxo-2- (2-oxoazepan-3-yl) isoindolin-4-yl) oxy) methyl) benzylcarbamate (674mg, 52% yield) as a white solid. MS (ESI) M/z 480.2[ M + H ]]⁺.

To tert-butyl (S) -4- (((1-oxo-2- (2-oxoazepan-3-yl) isoindolin-4-yl) oxy) methyl) benzylcarbamate (674mg,1.41mmol) at RT was added fluorobenzene/DMSO (30mL/5mL, containing 1 drop of H₂O in DMSO) was added Dess-Martin reagent (1.49g,3.52 mmol). The mixture was stirred at 80 ℃ for 16 hours. The mixture was cooled to RT and filtered. The filtrate was added to a cooled saturated aqueous solution of sodium thiosulfate (30mL), stirred at 0 ℃ for 5min, and then extracted with DCM. Workup and purification using 40% to 100% EtOAc/petroleum ether afforded (S) -4- (((2- (2, 7-dioxoazepan-3-yl) -1-oxoisoindolin-4-yl) oxy) methyl) benzylamino-methylTert-butyl ester (320mg, 46% yield) as a white solid. MS (ESI) M/z 494.2[ M + H ]]⁺.

To a solution of tert-butyl (S) -4- (((2- (2, 7-dioxoazepan-3-yl) -1-oxoisoindolin-4-yl) oxy) methyl) benzylcarbamate (22mg,0.0446mmol) in DCM (2mL) at RT was added TFA (0.5mL). The mixture was stirred at RT for 2 hours. Evaporation of the solvent afforded the desired product, which was lyophilized to afford compound 5 as a white solid (17.6mg, 78% yield). MS (ESI) M/z 394.1[ M +1 ]]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.71(s,1H),8.18(s,1H),7.55(d,J＝7.6Hz,2H),7.48-7.45(m,3H),7.33-7.30(m,2H),5.30(s,2H),5.23(dd,J＝4.8,12.4Hz,1H),4.48(s,2H),4.05(d,J＝5.2Hz,2H),3.11-3.05(m,1H),2.60-2.53(m,1H),2.34-2.31(m,1H),2.11-1.99(m,2H),1.85-1.80(m,1H).

Example 6

Compound 6: (S) -3- (4- { [ p- ({2- [3- (p- { 5-methyl-4- [ m- (tert-butylaminosulfonyl) phenyl) Amino group]-2-pyrimidinylamino } phenoxy) propylamino]Acetylamino } methyl) phenyl]Methoxy } -2-isoindolinoyl 2, 7-azacycloheptanediones

To a solution of (S) -3- (4- ((4- (aminomethyl) benzyl) oxy) -1-oxoisoindolin-2-yl) azepan-2, 7-dione (112mg,0.284mmol) in DCM (5mL) at RT was added TEA (24.2mg,0.175mmol) followed by 2-bromoacetyl chloride (45mg,0.284 mmol). The mixture was stirred for 1 hour. The solvent was evaporated and the residue was purified by silica gel chromatography, eluting with EtOAc/petroleum ether (20% to 100%) to give (S) -2-bromo-N- (4- (((2- (2, 7-dioxoazepan-3-yl) -1-oxoisoindolin-4-yl) oxy) methyl) benzyl) acetamide as a white solid. MS (ESI) M/z 514.1[ M + H ]]⁺.

To a solution of (S) -2-bromo-N- (4- (((2- (2, 7-dioxoazepan-3-yl) -1-oxoisoindolin-4-yl) oxy) methyl) benzyl) acetamide (45mg,0.0877mmol) in DMF (5mL) at RT was added K₂CO₃(24.2mg,0.175mmol) followed by 3- (2- ((4- (3-aminopropoxy) phenyl) amino) -5-methylpyrimidin-4-yl) amino) -N- (tert-butyl) benzenesulfonamide (45mg,0.0877 mmol). The mixture was heated at 50 ℃ for 2 hours. The solvent was evaporated and the residue was purified by prep-HPLC as described before to give compound 6 as a white solid (12.6mg, 16% yield). MS (ESI) M/z 917.7[ M + H ]]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.71(s,1H),8.77(s,1H),8.53(s,1H),8.12(d,J＝8.0Hz,2H),7.89(s,1H),7.55-7.41(m,9H),7.31-7.27(m,4H),6.77(d,J＝8.8Hz,2H),5.23-5.18(m,3H),4.44(s,2H),4.31(d,J＝5.6Hz,2H),3.96(t,J＝6.4Hz,2H),3.09-3.01(m,2H),2.74-2.67(m,2H),2.58-2.53(m,2H),2.32-2.26(m,1H),2.11(s,3H),2.04-1.97(m,3H),1.87-1.84(m,3H),1.12(s,9H).

Example 7

Compound 7: (S) -3- (6-fluoro-4- { [ p- (morpholinylmethyl) phenyl]Methoxy } -2-isoindolinyl) - 2, 7-azacycloheptanediones

To a cooled (-15 ℃) solution of 5-fluoro-2-methylbenzoic acid (1.0g,6.5mmol) in sulfuric acid (8mL) was added nitric acid (0.44mL) dropwise at RT. The mixture was stirred for 1 hour, then warmed to 0 ℃ and stirred for 1 hour. The mixture was poured slowly into ice water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄Dried, filtered and concentrated to give 5-fluoro-2-methyl-3-nitrobenzoic acid (830mg, crude) which was used in the next step without further purification.

Thionyl chloride (1mL) was added dropwise to a solution of 5-fluoro-2-methyl-3-nitrobenzoic acid (830mg crude) in MeOH (8mL) at 0 deg.C. The mixture was then heated to reflux for 3 hours. The solvent was evaporated to give the crude product which was purified by silica gel chromatography using petroleum ether/EtOAc (100: 1 to 50: 1) to give methyl 5-fluoro-2-methyl-3-nitrobenzoate as a yellow solid (530mg, 59% yield).

To methyl 5-fluoro-2-methyl-3-nitrobenzoate (530mg,2.66mmol) in MeOH (6mL) at RTPd/C (400mg) was added to the solution. At RT in H₂The suspension was stirred for 3 hours. The suspension was filtered through a pad of celite and the filtrate was concentrated to give methyl 3-amino-5-fluoro-2-methylbenzoate (420mg, crude) which was used in the next step without further purification.

Sulfuric acid (5mL) was added dropwise to water containing methyl 3-amino-5-fluoro-2-methylbenzoate (420mg,2.28mmol) at 0 deg.C, followed by sodium nitrate (165mg,2.39mmol in 2.5mL of water). After stirring at 0 ℃ for 2.5hr, the mixture was added dropwise to sulfuric acid (50% aqueous) at 100 ℃ and held for 20min, then the mixture was cooled to RT and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄Dried, filtered and concentrated to give methyl 5-fluoro-3-hydroxy-2-methylbenzoate which was used in the next step without further purification.

To a solution of methyl 5-fluoro-3-hydroxy-2-methylbenzoate (320mg,1.74mmol) in DMF (6mL) at 0 deg.C was added sodium hydride (60%, 84mg,2.1 mmol). The mixture was stirred at this temperature for 15min, then methyl iodide was added. After stirring at 0 ℃ for 15min, the mixture was warmed to RT and stirred for 1 h. The reaction was quenched with water and extracted with tert-butyl methyl ether. The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄Dried, filtered and concentrated to give methyl 5-fluoro-3-methoxy-2-methylbenzoate (327mg crude) which was used in the next step without further purification.

To a solution of methyl 5-fluoro-3-methoxy-2-methylbenzoate (5.4g,30.8mmol) in carbon tetrachloride (40mL) was added NBS (8.2g,46.3mmol) and 2,2' -azobis (2-methylpropanenitrile) (2.0mg,12.3mmol) at RT. The mixture was refluxed overnight, the solvent was evaporated, and the crude product was purified by silica gel chromatography (petroleum ether/EtOAc, 100: 1 to 20: 1) to give methyl 2- (bromomethyl) -5-fluoro-3-methoxybenzoate as a white solid (4.6g, 59% yield).

To a solution of (S) -3-aminoazepan-2-one (56mg,0.43mmol) and TEA (72mg,0.72mmol in DMF (2mL) was added a solution of methyl 2- (bromomethyl) -5-fluoro-3-methoxybenzoate (100mg,0.36mmol) in DMF (2mL) the mixture was stirred at 50 ℃ for 3hr, concentrated and washed with EtOAc to give (S) -6-fluoro-4-methoxy-2-(2-Oxoazepan-3-yl) isoindolin-1-one (100mg, 95% yield) as a white solid. MS (ESI) M/z 293.0[ M + H ]]⁺.

To a solution of (S) -6-fluoro-4-methoxy-2- (2-oxoazepan-3-yl) isoindolin-1-one (100mg,0.34mmol) in DCM (6mL) at 0 deg.C was added boron tribromide (515mg,2.05mmol in 2mL DCM). After stirring at this temperature for 15min, the mixture was warmed to RT and stirred for 3 h. The reaction was quenched with water at 0 ℃, concentrated, and purified by silica gel chromatography (DCM/MeOH, 100: 1 to 20: 1) to give (S) -6-fluoro-4-hydroxy-2- (2-oxoazepan-3-yl) isoindolin-1-one (20mg, 21% yield) as a white solid. MS (ESI) M/z 279.0[ M + H ]]⁺.

To a solution of (S) -6-fluoro-4-hydroxy-2- (2-oxoazepan-3-yl) isoindolin-1-one (250mg,0.90mmol) and (4- (diethoxymethyl) phenyl) MeOH (284mg,1.35mmol), triphenylphosphine (472mg,1.8mmol) in THF (2.5mL) at 0 deg.C was added DEAD (373mg,1.80 mmol). The mixture was stirred for 15min, warmed to RT and stirred for 1hr, the solvent was evaporated and the crude product was purified by silica gel chromatography (DCM/MeOH, 100: 1 to 50: 1) to give (S) -4- ((4- (diethoxymethyl) benzyl) oxy) -6-fluoro-2- (2-oxoazepan-3-yl) isoindolin-1-one (310mg, 73% yield) as a white solid.

To a solution of (S) -4- ((4- (diethoxymethyl) benzyl) oxy) -6-fluoro-2- (2-oxoazepan-3-yl) isoindolin-1-one (120mg,0.303mmol) in fluorobenzene/DMSO (24mL/6mL) was added Dess-Martin periodinane reagent (321.3mg,0.758 mmol). The mixture was stirred at 80 ℃ for 16 hours. After cooling to room temperature, Dess-Martin reagent (160mg) was added. The suspension was heated to 80 ℃ and continued for a further 16 hours. After cooling to RT, the reaction was quenched with saturated aqueous sodium thiosulfate (15mL) and stirred for 5 min. The resulting mixture was extracted with DCM. Work-up and purification with 10% to 69% EtOAc/petroleum ether gave (S) -4- ((2- (2, 7-dioxoazepan-3-yl) -6-fluoro-1-oxoisoindolin-4-yl) oxy) methyl) benzaldehyde (45mg, 36% yield) as a white solid. MS (ESI) M/z 411.1[ M + H ]]⁺.

To (S) -4- ((2- (2, 7-dioxoazepan-3-yl) at RT) -6-fluoro-1-oxoisoindolin-4-yl) oxy) methyl) benzaldehyde (30mg,0.076mmol) in DCM (4mL) was added morpholine (13mg,0.152mmol) followed by sodium triacetoxyborohydride (32mg,0.152 mmol). The mixture was stirred at RT for 16h, then the solvent was evaporated. The residue was purified by prep-tlc (etoac) to give the crude product, which was purified by prep-HPLC as described previously to give compound 7 as a white solid (5.5mg, 15% yield). MS (ESI) M/z 481.8[ M + H ]]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.72(s,1H),7.45(d,J＝7.2Hz,2H),7.34(d,J＝7.6Hz,2H),7.30(d,J＝8.1Hz,1H),7.11(d,J＝7.2Hz,1H),5.32-5.19(m,1H),5.24(s,2H),4.44(s,2H),3.57(s,4H),3.47(s,2H),3.21-3.06(m,1H),2.59-2.57(m,1H),2.34(s,5H),2.02-1.96(m,2H),1.82-1.75(m,1H).

Example 8

Compound 8: (S) -3- {4- [ (p-morpholinylcarbonylphenyl) methoxy]-2-isoindolinyl } -2, 7-aza Cycloheptanediones

To a solution of 4- (hydroxymethyl) benzoic acid (500mg,3.28mmol) in DMF (5mL) was added morpholine (326mg,3.94mmol) followed by HOBt (678.9mg,4.92mmol), EDAC & HCl (944mg,4.92mmol) and DIEA (846.2mg,6.56 mmol). The mixture was stirred at RT for 16 h. The reaction was diluted with water (5mL) and extracted with DCM. Work-up and purification with 30% to 90% EtOAc/petroleum ether afforded (4- (hydroxymethyl) phenyl) (morpholinyl) methanone (520mg, 72% yield) as a colorless oil. MS (ESI) M/z 221.1[ M + H ]]⁺.

To a solution of (S) -4-hydroxy-2- (2-oxoazepan-3-yl) isoindolin-1-one (100mg,0.385mmol), (4- (hydroxymethyl) phenyl) (morpholinyl) methanone (85mg,1.55mmol), and triphenylphosphine (201mg,0.77mmol) in THF (3mL) at 0 deg.C was added dropwise a solution of DEAD (134mg,0.77mmol) in THF (1 mL). The mixture was stirred at RT for 16 h. The solvent was evaporated and the residue was purified by preparative-TLC (EtOAc) to give (S) -4- ((4- (morpholine-4-carbonyl) benzyl) oxy) -2- (2-oxoazepan-3-yl) isoindoline-1-keto (135mg, 76% yield) as a white solid. MS (ESI) M/z 333.1[ M +1 ]]⁺.

To (S) -4- ((4- (morpholine-4-carbonyl) benzyl) oxy) -2- (2-oxoazepan-3-yl) isoindolin-1-one (135mg,0.292mmol) in fluorobenzene/DMSO (12mL/2mL, containing 1 drop of H₂O in DMSO) was added Dess-Martin periodinane (309.6mg,0.73 mmol). The suspension was stirred at 80 ℃ overnight, cooled to RT, filtered and the filtrate was added to saturated aqueous sodium thiosulfate (10 mL). After stirring at 0 ℃ for 5min, the mixture was extracted with DCM. With 10% sodium thiosulfate/saturated NaHCO₃(1:1) washing the combined organic layers with brine, and passing over anhydrous Na₂SO₄Drying, filtration and concentration gave the crude product, which was purified by prep-tlc (etoac) to give compound 8 as a white solid (52.5mg, 38% yield). MS (ESI) M/z 333.1[ M + H ]]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.68(s,1H),7.57(d,J＝8.0Hz,2H),7.51-7.44(m,3H),7.33(d,J＝8.0Hz,2H),5.31(s,2H),5.23(dd,J＝5.2,12.4Hz,1H),4.49(s,2H),3.60(s,6H),3.11-3.03(m,1H),2.60-2.54(m,1H),2.38-2.29(m,1H),2.12-1.98(m,2H),1.86-1.76(m,1H).

Example 9

Compound 9: (S) -3- (4- { [ m- (aminomethyl) phenyl]Methoxy } -2-isoindolinyl) -2, 7-aza Cycloheptanedione trifluoroacetic acid

To a solution of (S) -4-hydroxy-2- (2-oxoazepan-3-yl) isoindolin-1-one (150mg,0.577mmol), 3- (hydroxymethyl) benzonitrile (154mg,1.15mmol) and triphenylphosphine (378mg,1.44mmol) in THF (3.5mL) at RT was added DEAD (251mg,1.44 mmol). The mixture was stirred for 30 min. The solvent was evaporated and the residue was purified by preparative-TLC (DCM/MeOH, 100: 1 to 30: 1) to give (S) -3- (((1-oxo-2- (2-oxoazepan-3-yl) isoindolin-4-yl) oxy) methyl) benzonitrile (235mg, 81% yield) as a white solid. MS (ESI) M/z376.2[ M + H ]]⁺.

To (S) -3- (((1-oxo) at RT-2- (2-Oxoazepan-3-yl) isoindolin-4-yl) oxy) methyl) benzonitrile (200mg,0.48mmol) in fluorobenzene/DMSO (15mL/2mL) was added Dess-Martin periodinane (508mg,1.2 mmol). The mixture was heated to 80 ℃ overnight and cooled to RT and 20mL of saturated sodium thiosulfate solution was added and the mixture was extracted with DCM. Work-up afforded the crude product, which was washed with tert-butyl methyl ether to give (S) -3- ((2- (2, 7-dioxoazepan-3-yl) -1-oxoisoindolin-4-yl) oxy) methyl) benzonitrile (120mg, 58% yield) as a white solid. MS (ESI) M/z 390.1[ M + H ]]⁺.

To a solution of (S) -3- ((2- (2, 7-dioxoazepan-3-yl) -1-oxoisoindolin-4-yl) oxy) methyl) benzonitrile (130mg,0.334mmol) in THF (8mL) at RT was added di-tert-butyl dicarbonate (146mg,0.668mmol) and Raney Ni (60 mg). Degassing and using H₂After purging, the mixture was stirred at RT overnight. The suspension was filtered through a pad of celite. The filtrate was concentrated and purified by preparative-TLC (EtOAc) to give tert-butyl (S) -3- (((2- (2, 7-dioxoazepan-3-yl) -1-oxoisoindolin-4-yl) oxy) methyl) benzylcarbamate as a white solid (150mg, 59%)

To a solution of tert-butyl (S) -3- (((2- (2, 7-dioxoazepan-3-yl) -1-oxoisoindolin-4-yl) oxy) methyl) benzylcarbamate (75mg,0.152mmol) in DCM (2mL) at RT was added TFA (1 mL). The mixture was stirred at RT for 30 min. The solvent was evaporated and the residue was lyophilized to give compound 9 as a white solid (40mg, 66% yield). MS (ESI) M/z 394.2[ M + H ]]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.73(s,1H),8.18(s,3H),7.58-7.43(m,5H),7.34(d,J＝7.2Hz,2H),5.28-5.23(m,3H),4.80(m,2H),4.10-4.07(m,2H),3.08-3.06(m,1H),2.60-2.55(m,1H),2.32-2.29(m,1H),2.12-1.99(m,2H),1.80-1.77(m,1H).

Example 10

Compound 10: (S) -3- (4- { [ m- (morpholinomethyl) phenyl]Methoxy } -2-isoindolinyl) -2,7- Azepane diones

To a solution of (S) -4-hydroxy-2- (2-oxoazepan-3-yl) isoindolin-1-one (160mg,0.615mmol), 1, 3-phenylenedimethanol (170mg,1.23mmol), and triphenylphosphine (402mg,1.538mmol) in THF (8mL) at RT was added DEAD (268mg,1.53 mmol). The mixture was stirred at RT for 30 min. The solvent was evaporated and the residue was purified by preparative-TLC (DCM/MeOH, 100: 1 to 30: 1) to give (S) -4- ((3- (hydroxymethyl) benzyl) oxy) -2- (2-oxoazepan-3-yl) isoindolin-1-one (156mg, 59% yield) as a white solid. MS (ESI) M/z 381.2[ M + H ]]⁺.

To a solution of (S) -4- ((3- (hydroxymethyl) benzyl) oxy) -2- (2-oxoazepan-3-yl) isoindolin-1-one (138mg,0.363mmol) in fluorobenzene/DMSO (4mL/1mL) at RT was added Dess-Martin periodinane (462mg,1.09 mmol). After stirring at 80 ℃ overnight, the mixture was cooled to RT and then 20mL of saturated sodium thiosulfate solution was added and the mixture was extracted with DCM. Work-up provided the crude product which was washed with tert-butyl methyl ether to give (S) -3- (((2- (2, 7-dioxoazepan-3-yl) -1-oxoisoindolin-4-yl) oxy) methyl) benzaldehyde (85mg, 60% yield) as a white solid. MS (ESI) M/z391.2[ M + H ]]⁺.

To a solution of (S) -3- ((2- (2, 7-dioxoazepan-3-yl) -1-oxoisoindolin-4-yl) oxy) methyl) benzaldehyde (80mg,0.204mmol) and morpholine (36mg,0.408mmol) in DCM (4mL) at RT was added NaBH (OAc)₃(87mg,0.408 mmol). The mixture was stirred overnight. The solvent was evaporated and the residue was purified by preparative-TLC using DCM/MeOH (10: 1) to give compound 10 as a white solid (30.5mg, 32% yield). MS (ESI) M/z464.2[ M + H ]]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.73(s,1H),7.49-7.27(m,7H),5.27-5.22(m,3H),4.47(s,2H),3.56(s,4H),3.48(s,2H),3.12-3.05(m,1H),2.58(d,J＝16.8Hz,1H),2.34(s,5H),2.12-2.06(m,1H),2.04-1.99(m,1H),1.82-1.7 8(m,1H).

Example 11

Compound 11: (S) -3- (4- { [ p- (morpholinomethyl) phenyl]Methoxy } -3-oxo-2H-isoindole-2-yl 2, 7-azacycloheptanediones

To a solution of 3-methoxyphthalic acid (3.0g,15.306mmol) in THF (24mL) was added acetic anhydride (10mL) at RT. The mixture was stirred at 80 ℃ for 3 hours. Evaporation of the solvent gave 4-methoxyisobenzofuran-1, 3-dione (2.72g, quantitative yield) as a white solid. MS (ESI) M/z 178.9[ M + H ]]⁺.

To a solution of (S) -3-aminoazepan-2-one (1.96g,15.28mmol) in AcOH/ACN (28mL/20mL) at RT was added 4-methoxyisobenzofuran-1, 3-dione (2.71g,15.28 mmol). The mixture was stirred at 85 ℃ overnight and then cooled to RT. Sodium acetate (3.13g,38.20mmol) was added followed by AcOH (12 mL). The mixture was stirred at 85 ℃ overnight. The solvent was evaporated, then the residue was diluted with water (30mL) and stirred at RT for 30 min. The resulting suspension was filtered and the filter cake was washed with EtOAc to give (S) -4-methoxy-2- (2-oxoazepan-3-yl) isoindoline-1, 3-dione (2.154g, 49% yield) as a white solid. MS (ESI) M/z 289.1[ M + H ]]⁺.

To a solution of (S) -4-methoxy-2- (2-oxoazepan-3-yl) isoindoline-1, 3-dione (2.1g,7.292mmol) in DCM (40mL) at 0 deg.C is added tribromoborane (3.4mL) in DCM (10mL) dropwise. After stirring at RT for 3h, the mixture was diluted with ice water and extracted with DCM. The combined organic layers were washed with brine, over anhydrous Na₂SO₄Drying, filtration and concentration gave the crude product, which was washed with EtOAc to give (S) -4-hydroxy-2- (2-oxoazepan-3-yl) isoindoline-1, 3-dione (1g, 50% yield) as a pale yellow solid. MS (ESI) M/z 275.0[ M + H ]]⁺.

To a solution of (S) -4-hydroxy-2- (2-oxoazepan-3-yl) isoindoline-1, 3-dione (300mg,1.095mmol), 1, 4-phenylenedimethanol (272mg,1.971mmol), and triphenylphosphine (574mg,2.190mmol) in THF (5mL) at 0 deg.C was added DEAD (381mg,2.19 mmol). The mixture was stirred at RT overnight. The solvent was evaporated and the crude product was purified by silica gel chromatography using EtOAc/petroleum ether (20% to 96%) to afford(S) -4- ((4- (hydroxymethyl) benzyl) oxy) -2- (2-oxoazepan-3-yl) isoindoline-1, 3-dione (168mg, 39% yield) as a white solid. MS (ESI) M/z 395.1[ M + H ]]⁺.

To a solution of (S) -4- ((4- (hydroxymethyl) benzyl) oxy) -2- (2-oxoazepan-3-yl) isoindoline-1, 3-dione (140mg,0.355mmol) in 1, 2-dichloroethane/DMSO (12mL/2mL) at RT was added Dess-Martin reagent (753mg,1.775 mmol). The mixture was stirred at 80 ℃ overnight. The mixture was cooled to RT and filtered, and the filtrate was quenched with saturated sodium thiosulfate solution (15 mL). After stirring for 10min, the mixture was extracted with DCM. Work-up and purification using 20% to 96% EtOAc/petroleum ether gave (S) -4- ((2- (2, 7-dioxoazepan-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) methyl) benzaldehyde (95mg, 54% yield) as a yellow solid.

To a solution of (S) -4- ((2- (2, 7-dioxoazepan-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) methyl) benzaldehyde (75mg,0.1847mmol) in DCM (3mL) was added morpholine (32mg,0.3694mmol) and sodium triacetoxyborohydride (78mg,0.3694mmol) at RT and the mixture was stirred overnight. The solvent was evaporated and the crude product was purified by prep-TLC using DCM/MeOH (10: 1) to give compound 11 as a white solid (42mg, 48% yield). MS (ESI) M/z 477.8[ M + H ]]⁺.1H NMR(DMSO-d₆,400MHz)δ：10.84(s,1H),7.82-7.35(m,7H),5.35(s,2H),5.19-5.15(m,1H),3.60-3.50(m,4H),3.50-3.40(m,2H),3.14-3.07(m,1H),2.70-2.60(m,1H),2.35(s,4H),2.19-1.87(m,4H).

Example 12

Compound 12: (S) -3- (4- { [ p- (morpholinomethyl) phenyl]Methoxy } -2-isoindolinyl) -2,5- Pyrrolidinediones

To a stirred solution of (S) -4-amino-2- ((tert-butoxycarbonyl) amino) -4-oxobutanoic acid (2.0g,8.6mmol) in THF (10mL) and MeOH (10mL) at 0 deg.C was added dropwise a solution of (trimethylsilyl) diazomethane (2M in hexane, 6.5 mL). The mixture was stirred at 0 ℃ for 1 hour, then concentrated to give methyl (S) -4-amino-2- ((tert-butoxycarbonyl) amino) -4-oxobutanoate (crude) as a colorless oil.

To a stirred solution of methyl (S) -4-amino-2- ((tert-butoxycarbonyl) amino) -4-oxobutanoate (8.6mmol) in DCM (6mL) at RT was added TFA (3 mL). After stirring overnight, the mixture was concentrated to give methyl (S) -2, 4-diamino-4-oxobutanoate which was used directly in the next step.

To a solution of methyl (S) -2, 4-diamino-4-oxobutanoate (8.6mmol) and methyl 2- (bromomethyl) -3-methoxybenzoate (2.2g,8.6mmol) in DMF (20mL) was added TEA (3.6 mL). After stirring at 50 ℃ for 5h, the mixture was diluted with water and extracted with EtOAc. Work-up and purification using EtOAc/petroleum ether (20% to 80%) afforded (S) -methyl 4-amino-2- (4-methoxy-1-oxoisoindolin-2-yl) -4-oxobutanoate as a yellow solid (1.2g, 48% yield). MS (ESI) M/z 293.0[ M + H ]]⁺.

Boron tribromide (2.3mL) was added dropwise to a solution of methyl (S) -4-amino-2- (4-methoxy-1-oxoisoindolin-2-yl) -4-oxobutanoate (1.2g,4.1mmol) in DCM (12mL) at 0 deg.C. The mixture was stirred at RT for 2 hours and quenched with water and MeOH. The solvent was evaporated and the residue was purified by silica gel chromatography (DCM/MeOH, 20: 1) to give (S) -4-amino-2- (4-hydroxy-1-oxoisoindolin-2-yl) -4-oxobutanoic acid (3g, crude) as a yellow solid. MS (ESI) M/z 265.0[ M + H ]]⁺.

To a solution of (S) -4-amino-2- (4-hydroxy-1-oxoisoindolin-2-yl) -4-oxobutanoic acid (3g of crude) in THF (15mL) and MeOH (15mL) at 0 deg.C was added dropwise a solution of (trimethylsilyl) diazomethane (2M in hexane, 6.8 mL). The mixture was stirred at 0 ℃ for 1.5h and concentrated. The residue was purified by silica gel chromatography (DCM/MeOH, 10: 1) to give methyl (S) -4-amino-2- (4-hydroxy-1-oxoisoindolin-2-yl) -4-oxobutanoate (470mg, 43% yield) as a white solid. MS (ESI) M/z 279.0[ M + H ]]⁺.

To methyl (S) -4-amino-2- (4-hydroxy-1-oxoisoindolin-2-yl) -4-oxobutanoate (300mg,1.08mmol), (4- (morpholinylmethyl) phenyl) methanol (335mg, 1) at 0 ℃.62mmol) and triphenylphosphine (567mg,2.16mmol) in THF (8mL) DEAD (376mg,2.16mmol) was added and the mixture was stirred at RT overnight. The solvent was evaporated and the residue was purified by preparative-TLC (DCM/MeOH, 10: 1) to give methyl (S) -4-amino-2- (4- (4- (morpholinylmethyl) benzyl) oxy) -1-oxoisoindolin-2-yl) -4-oxobutanoate (150mg, 30% yield) as a white solid. MS (ESI) M/z 468.1[ M + H ]]⁺.

To a solution of methyl (S) -4-amino-2- (4- ((4- (morpholinylmethyl) benzyl) oxy) -1-oxoisoindolin-2-yl) -4-oxobutanoate (100mg,0.21mmol) in THF (6mL) at RT was added lithium hydroxide (11mg,0.42 mmol). The mixture was stirred for 3 hours, then diluted with water and adjusted to pH 3 with 1N HCl. Work-up and purification using preparative-TLC (DCM/MeOH, 10: 1) gave compound 12 as a yellow solid (13mg, 14% yield). MS (ESI) M/z 453.9[ M + H ]]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.49(brs,1H),7.51-7.44(m,3H),7.34-7.30(m,4H),5.27(t,J＝8.0Hz,1H),5.23(s,2H),4.61(d,J＝17.2Hz,1H),4.27(d,J＝17.2Hz,1H),3.57(t,J＝4.0Hz,4H),3.46(s,2H),2.94(d,J＝7.6Hz,2H),2.34(s,4H).

Example 13

Compound 13: (S) -3- (4- { [ p- ({3- [3- (p- { 5-methyl-4- [ m- (tert-butylaminosulfonyl) benzene) Radical amino]-2-pyrimidinylamino } phenoxy) propyl]Ureido } methyl) phenyl]Methoxy } -2-isoindolinyl) -2,7- Azepane diones

To a solution of tert-butyl 3- (4- ((4- ((3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenoxy) propyl) carbamate (100mg,0.171mmol) in anhydrous DCM (8mL) at 0 ℃ was added TFA (2 mL). The reaction was stirred at RT for 16 h. The solvent was evaporated and the residue dried to give amine TFA salt (100mg, crude). The amine TFA salt was dissolved in THF (5mL) and TEA (34.5mg,0.342mmol) was added at RT followed by 4-nitrobenzyl chloroformate (34.2mg,0.171 mmol). The mixture was stirred for 1 hour. Evaporation ofSolvent to give 4-nitrophenyl 3- (4- ((4- ((3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenoxy) propyl) carbamate (30mg, crude) which was used directly in the next step. MS (ESI) M/z 650.2[ M + H ]]⁺.

To a solution of tert-butyl (S) -4- ((2- (2, 7-dioxoazepan-3-yl) -1-oxoisoindolin-4-yl) oxy) methyl) benzylcarbamate (23mg,0.046mmol) in DCM (4mL) at RT was added TFA (1 mL). The solvent was evaporated and the residue dried to give amine TFA salt (30mg, crude) as a yellow gum. The amine TFA salt was dissolved in THF (5mL) and TEA (10mg,0.092mmol) was added at RT followed by a suspension of 4-nitrophenyl (3- (4- ((4- ((3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenoxy) propyl) carbamate (30mg,0.046mmol) in THF (1 mL). The reaction was stirred at 60 ℃ for 3 hours. The solvent was evaporated and the residue was purified by silica gel chromatography, eluting with MeOH/DCM (0% to 9%) to give compound 13 as a white solid (22.3mg, 53% yield). MS (ESI) M/z903.7[ M + H ]]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.72(s,1H),8.82(s,1H),8.57(s,1H),8.15-8.12(m,2H),7.89(s,1H),7.59(s,1H),7.54-7.41(m,7H),7.31-7.25(m,4H),6.79(d,J＝8.8Hz,2H),6.37(t,J＝6.0Hz,1H),6.06(t,J＝5.2Hz,1H),5.23-5.19(m,3H),4.45(s,2H),4.21(d,J＝6.4Hz,2H),3.91(t,J＝5.6Hz,2H),3.19-3.15(m,2H),3.09-3.02(m,1H),2.58-2.54(m,1H),2.35-2.31(m,1H),2.11(s,3H),2.04-1.97(m,1H),1.82-1.78(m,3H),1.12(s,9H).

Example 14

Compound 14: (S) -3- (4- { [ p- (morpholinomethyl) phenoxy]Methyl } -2-isoindolinyl) -2,7- Azepane diones

To a solution of (S) -1-oxo-2- (2-oxoazepan-3-yl) isoindoline-4-carbaldehyde (910mg,3.35mmol) in THF (25mL) at RT was added sodium borohydride (254mg,6.70 mmol). The mixture was stirred for 2 hours. The reaction was concentrated to give the crude product which was passed through silica gelPurification by chromatography eluting with MeOH/DCM (1: 10) gave (S) -4- (hydroxymethyl) -2- (2-oxoazepan-3-yl) isoindolin-1-one (539mg, 59% yield) as a white solid. MS (ESI) M/z 275.1[ M + H ]]⁺.

To a solution of (S) -4- (hydroxymethyl) -2- (2-oxoazepan-3-yl) isoindolin-1-one (539mg,1.97mmol), 4-hydroxybenzaldehyde (288mg,2.36mmol) and triphenylphosphine (1.03g,3.93mmol) in THF (30mL) at 0 deg.C was added DEAD (685mg,3.93 mmol). The mixture was stirred for 15min, then warmed to RT and stirred overnight. The solvent was evaporated to give the crude product, which was purified by silica gel chromatography eluting with MeOH/DCM (0% to 5%) to give (S) -4- ((1-oxo-2- (2-oxoazepan-3-yl) isoindolin-4-yl) methoxy) benzaldehyde (520mg, 70% yield) as a white solid. MS (ESI) M/z 379.1[ M + H ]]⁺.

To a solution of (S) -4- ((1-oxo-2- (2-oxoazepan-3-yl) isoindolin-4-yl) methoxy) benzaldehyde (520mg,1.38mmol) in fluorobenzene/DMSO (24mL/4mL, DMSO with 1 drop of water) was added Dess-Martin reagent (1.46g,3.44 mmol). The suspension was heated at 80 ℃ for 18 hours. The suspension was cooled to RT and then added to saturated aqueous sodium thiosulfate (20mL) at 0 ℃ and stirred for 5min before being extracted with DCM. Work-up and purification using 20% to 96% EtOAc/petroleum ether gave (S) -4- ((2- (2, 7-dioxoazepan-3-yl) -1-oxoisoindolin-4-yl) methoxy) benzaldehyde (174.2mg, 32% yield) as a white solid. MS (ESI) M/z 393.1[ M + H ]]⁺.

To a solution of (S) -4- ((2- (2, 7-dioxoazepan-3-yl) -1-oxoisoindolin-4-yl) methoxy) benzaldehyde (100mg,0.255mmol) in THF (5mL) at RT was added morpholine (88mg,1.02mmol) followed by sodium cyanoborohydride (64mg,1.02 mmol). The mixture was stirred for 2 hours. The solvent was evaporated and the residue was purified by prep-HPLC as described before to give compound 14 as a white solid (22.1mg, 19% yield). MS (ESI) M/z 498.1[ M + H ]]⁺.¹H NMR(DMSO-d₆,400MHz)δ：10.76(s,1H),7.73-7.71(m,2H),7.55(t,J＝7.6Hz,1H),7.23(d,J＝8.4Hz,2H),7.01(d,J＝8.4Hz,2H),5.25(s,2H),4.63(s,2H),3.55(s,4H),3.36(s,2H),3.13-3.06(m,1H),2.59-2.55(m,1H),2.32(s,4H),2.17-1.97(m,3H),1.86-1.76(m,1H).

Example 15

Compound 15: (S) -3- (5- { [ p- (morpholinomethyl) phenyl]Methoxy } -2-isoindolinyl) -2,7- Azepane diones

NBS (10g,55.57mmol) and 2,2' -azobis (2-methylpropanenitrile) (4.0mg,9.43mmol) were added to a solution of methyl 4-methoxy-2-methylbenzoate (10g,55.56mmol) in carbon tetrachloride (150mL) at RT. The mixture was stirred at reflux for 6 hours. The solvent was evaporated to give the crude product which was purified by silica gel chromatography (EtOAc/petroleum ether, 1:20 to 1:5) to give methyl 2- (bromomethyl) -4-methoxybenzoate (13.6g, 94% yield) as a white solid.

To a solution of (S) -3-aminoazepan-2-one (1.6g,12.4mmol) in DMF (16mL) at RT was added TEA (2.9mL,20.6mmol) and methyl 2- (bromomethyl) -4-methoxybenzoate (2.7g,10.3mmol) in 4mL DMF. The mixture was stirred at 85 ℃ overnight. The solvent was evaporated and the crude product was purified by silica gel chromatography (DCM/MeOH, 50: 1) to give (S) -5-methoxy-2- (2-oxoazepan-3-yl) isoindolin-1-one (1.39g, 49% yield) as a white solid. MS (ESI) M/z 275.0[ M + H ]]⁺.

To a solution of (S) -5-methoxy-2- (2-oxoazepan-3-yl) isoindolin-1-one (1.0g,3.65mmol) in DCM (12mL) at 0 deg.C was added boron tribromide (2.0mL,21.89mmol in 4mL DCM) dropwise. The mixture was stirred at this temperature for 30 minutes, then warmed to RT for 2 hours and quenched with water and MeOH. The solvent was evaporated and the residue was purified by silica gel chromatography (DCM/MeOH, 20: 1) to give (S) -5-hydroxy-2- (2-oxoazepan-3-yl) isoindolin-1-one (1.7g crude) as a white solid. MS (ESI) M/z 261.0[ M + H ]]⁺.

To (S) -5-hydroxy-2- (2-oxoazepan-3-yl) isoindolin-1-one (500mg,1.92mmol), 1, 4-phenylenedimethanol (1.0g,7.68 m) at RTmol) and triphenylphosphine (2.0g,7.68mmol) in THF (2mL) DEAD (1.3mg,7.68mmol) was added. The mixture was stirred for 2 hours. The solvent was evaporated and the residue was purified by silica gel chromatography (DCM/MeOH, 50: 1 to 20: 1) to give (S) -5- ((4- (hydroxymethyl) benzyl) oxy) -2- (2-oxoazepan-3-yl) isoindolin-1-one as a white solid (90mg, 12% yield). MS (ESI) M/z 381.1[ M + H ]]⁺.

To a solution of (S) -5- ((4- (hydroxymethyl) benzyl) oxy) -2- (2-oxoazepan-3-yl) isoindolin-1-one (60mg,0.157mmol) in fluorobenzene/DMSO (6.0mL/1.5mL) at RT was added Dess-Martin periodinane (268mg,0.631 mmol). After stirring at 80 ℃ overnight, the mixture was cooled to RT, then 20mL of saturated sodium thiosulfate solution was added and the mixture was stirred at RT for 5 min. Work-up and purification by preparative-TLC using hexane/EtOAc (1:1) afforded (S) -4- ((2- (2, 7-dioxoazepan-3-yl) -1-oxoisoindolin-5-yl) oxy) methyl) benzaldehyde (15mg, 16% yield) as a white solid. MS (ESI) M/z 393.0[ M + H ]]⁺.

To a solution of (S) -4- ((2- (2, 7-dioxoazepan-3-yl) -1-oxoisoindolin-5-yl) oxy) methyl) benzaldehyde (15mg,0.038mmol) and morpholine (7mg,0.076mmol) in DCM at RT was added sodium triacetoxyborohydride (16mg,0.076 mmol). The mixture was stirred for 28 hours. The solvent was evaporated and the crude product was purified by preparative-TLC using DCM/MeOH (10: 1) to give compound 15 as a white solid (6.5mg, 38% yield). MS (ESI) M/z464.2[ M + H ]]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.71(s,1H),7.64(d,J＝8.4Hz,1H),7.43(d,J＝8.0Hz,2H),7.34(d,J＝8.0Hz,2H),7.27(s,1H),7.13(d,J＝8.8Hz,1H),5.23-5.19(m,3H),4.48-4.47(m,2H),3.58-3.56(m,4H),3.47(s,2H),3.08-3.06(m,1H),2.60-2.51(m,1H),2.35(s,4H),2.27-2.24(m,1H),2.10-2.00(m,2H),1.80-1.77(m,1H).

Example 16

Compound 16: (S) -6- (4- { [ p- (morpholinomethyl) phenyl]Methoxy } -2-isoindolinyl) -1,4- Oxaazacycloheptane-3, 5-diones

Thionyl chloride was added dropwise to a solution of 3-hydroxy-2-methylbenzoic acid (20g,0.13mmol) in MeOH (240mL) at 0 deg.C, and the mixture was stirred at reflux for 3 hr. The solvent was evaporated and the residue was purified by silica gel chromatography (petroleum ether/EtOAc, 20: 1 to 5: 1) to give methyl 3-hydroxy-2-methylbenzoate (18.7g, 86% yield) as a yellow solid.

To a solution of methyl 3-hydroxy-2-methylbenzoate (18.7g,0.11mol) and imidazole (19.0g,0.25mol) in DMF (28mL) at RT was added tert-butyldimethylchlorosilane (20.4g,0.12 mol). After stirring at 60 ℃ for 3 hours, the mixture was cooled to RT and extracted with tert-butyl methyl ether. The combined organic layers were passed over anhydrous Na₂SO₄Dried, filtered and concentrated to give methyl 3- ((tert-butyldimethylsilyl) oxy) -2-methylbenzoate (32g crude) as a yellow solid which was used in the next step without further purification.

To a solution of methyl 3- ((tert-butyldimethylsilyl) oxy) -2-methylbenzoate (5.0g,17.8mmol) in carbon tetrachloride (30mL) was added NBS (4.7g,26.8mmol) and 2,2' -azobis (2-methylpropanenitrile) (1.1g,7.1mmol) at RT. The suspension was stirred at reflux for 5 hours. The solvent was evaporated and the residue was purified by silica gel chromatography (petroleum ether/EtOAc, 100: 1 to 50: 1) to give methyl 2- (bromomethyl) -3- ((tert-butyldimethylsilyl) oxy) benzoate (5.8g, 90% yield) as a yellow oil.

To a solution of methyl 2- (bromomethyl) -3- ((tert-butyldimethylsilyl) oxy) benzoate (490mg,1.4mmol) in DMF (6mL) at RT was added TEA (0.4mL,2.8mmol) and (S) -6-amino-1, 4-oxazepan-5-one (200mg,1.5mmol in 2mL DMF). The mixture was stirred at RT for 4 hours, then heated to 80 ℃ and overnight. The mixture was concentrated and the residue diluted with THF (10 mL). TBAF (200mg,0.76mmol) was added and the mixture was stirred at reflux for 2 h. The solvent was evaporated and the residue was purified by silica gel chromatography (DCM/MeOH, 50: 1 to 20: 1) to give (S) -6- (4-hydroxy-1-oxoisoindolin-2-yl) -1, 4-oxazepan-5-one (183mg, 50% yield) as a white solid. MS (ESI) M/z 263.0[ M ]+H]⁺.

To a solution of (S) -6- (4-hydroxy-1-oxoisoindolin-2-yl) -1, 4-oxazepan-5-one (230mg,0.87mmol), 1, 4-phenylenedimethanol (182mg,1.31mmol), and triphenylphosphine (568mg,2.17mmol) in THF (2.5mL) at RT was added DEAD (377mg,2.17 mmol). The mixture was stirred at RT for 3 hours. The solvent was evaporated and the crude product was purified by silica gel chromatography (DCM/MeOH, 100: 1 to 20: 1) to give (S) -6- (4- ((4- (hydroxymethyl) benzyl) oxy) -1-oxoisoindolin-2-yl) -1, 4-oxazepan-5-one as a white solid (110mg, 33% yield). MS (ESI) M/z 383.1[ M + H ]]⁺.

To a solution of (S) -6- (4- ((4- (hydroxymethyl) benzyl) oxy) -1-oxoisoindolin-2-yl) -1, 4-oxazepan-5-one (110mg,0.288mmol) in ACN/DMSO (8mL/2mL) at RT was added Dess-Martin periodinane (732mg,1.72 mmol). The mixture was stirred at 80 ℃ for 4 hours, then cooled to RT and 20mL of saturated sodium thiosulfate solution was added, then stirred for 5 min. The mixture was extracted with DCM. With DCM then DCM/EtOAc, 5:1 to 1:1 to yield (S) -4- (((2- (3, 5-dioxo-1, 4-oxazepan-6-yl) -1-oxoisoindolin-4-yl) oxy) methyl) benzaldehyde (58mg, 51% yield) as a white solid. MS (ESI) M/z 395.0[ M + H ]]⁺.

To a solution of (S) -4- ((2- (3, 5-dioxo-1, 4-oxazepan-6-yl) -1-oxoisoindolin-4-yl) oxy) methyl) benzaldehyde (58mg,0.147mmol) and morpholine (26mg,0.294mmol) in DCM (1.5mL) at RT was added sodium triacetoxyborohydride (64mg,0.294 mmol). The mixture was stirred at RT for 4 hours and then concentrated. The crude product was purified by prep-TLC using DCM/MeOH (10: 1) to give compound 16 as a white solid (19mg, 20% yield). MS (ESI) M/z 465.9[ M + H ]]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.11(s,1H),7.48-7.44(m,3H),7.35-7.32(m,4H),5.67-5.66(m,1H),5.24(s,2H),4.71(d,J＝17.2Hz,1H),4.55(d,J＝10.4Hz,2H),4.40-4.35(m,2H),4.06-4.05(m,1H),3.57-3.55(m,4H),3.47(s,2H),2.35(s,4H).

Example 17

Compound 17: 3- (4- { [ p- ({2- [3- (p- { 5-methyl))-4- [ m- (tert-butylaminosulfonyl) phenylamino Base of]-2-pyrimidinylamino } phenoxy) propylamino]Acetylamino } methyl) phenyl]Methoxy } -2-isoindolinoyl 2, 6-piperidinedione

Thionyl chloride (30mL,0.41mol) was added dropwise to a solution of 3-hydroxy-2-methylbenzoic acid (20g,0.13mol) in MeOH (240mL) at 0 deg.C. The mixture was stirred at reflux for 3 hours. The solvent was evaporated and the residue was purified by silica gel chromatography using petroleum ether/EtOAc (20: 1 to 5: 1) to give methyl 3-hydroxy-2-methylbenzoate (18.7g, 86% yield) as a yellow solid.

To a solution of methyl 3- ((tert-butyldimethylsilyl) oxy) -2-methylbenzoate (3.0g,10.7mmol) in carbon tetrachloride (22mL) was added NBS (2.9g,16.0mmol) and 2,2' -azobis (2-methylpropanenitrile) (701mg,4.3mmol) at RT. The mixture was stirred at 80 ℃ for 5 hours. Evaporation of the solvent gave the crude product which was purified by silica gel chromatography (petroleum ether/EtOAc, 30: 1) to give methyl 2- (bromomethyl) -3- ((tert-butyldimethylsilyl) oxy) benzoate as a yellow oil (3.7g 97%).

To a solution of methyl 2- (bromomethyl) -3- ((tert-butyldimethylsilyl) oxy) benzoate (1.0g,2.77mmol) and TEA (0.8mL,5.54mmol) in DMF (6mL) at RT was added a solution of tert-butyl 2, 5-diamino-5-oxopentanoate (670mg,3.32mmol) in DMF (4 mL). The mixture was stirred for 2 hours, then heated to 80 ℃ and stirred overnight. Evaporating the solvent to obtain a crude product, said crude productThe product was purified by silica gel chromatography (DCM/MeOH, 100: 1 to 50: 1) to give tert-butyl 5-amino-4- (4-hydroxy-1-oxoisoindolin-2-yl) -5-oxopentanoate as a white solid (820mg, 88% yield). MS (ESI) M/z 279.0[ M + H-56 ]]⁺.

To a solution of tert-butyl 5-amino-4- (4-hydroxy-1-oxoisoindolin-2-yl) -5-oxopentanoate (450mg,1.34mmol), 4- (hydroxymethyl) benzonitrile (360mg,2.69mmol) and triphenylphosphine (1.4g,5.36mmol) in THF (2mL) at RT was added DEAD (932mg,5.36mmol) dropwise. The mixture was stirred at RT for 4 hours. The solvent was evaporated and the crude product was purified by silica gel chromatography (DCM/MeOH, 100: 1 to 20: 1) to give tert-butyl 5-amino-4- (4- ((4-cyanobenzyl) oxy) -1-oxoisoindolin-2-yl) -5-oxopentanoate as a white solid (290mg, 39% yield). MS (ESI) M/z394.0[ M + H-56 ]]⁺.

To a solution of tert-butyl 5-amino-4- (4- ((4-cyanobenzyl) oxy) -1-oxoisoindolin-2-yl) -5-oxopentanoate (200mg,0.45mmol) in DCM (6mL) at RT was added TFA (1.5 mL). The mixture was stirred at RT for 5h, then concentrated to give 5-amino-4- (4- ((4-cyanobenzyl) oxy) -1-oxoisoindolin-2-yl) -5-oxopentanoic acid TFA salt (250mg crude) as a white solid, which was used in the next step without further purification. MS (ESI) M/z394.0[ M + H ]]⁺.

To a solution of 5-amino-4- (4- ((4-cyanobenzyl) oxy) -1-oxoisoindolin-2-yl) -5-oxopentanoic acid TFA salt (250mg,0.45mmol) in ACN (8mL) at RT was added CDI (291mg,1.80 mmol). The mixture was stirred at 95 ℃ for 6 hours. Evaporation of the solvent gave a crude product which was purified by silica gel chromatography (DCM/MeOH, 100: 1 to 50: 1) to give 4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) methyl) benzonitrile (130mg 77%) as a white solid. MS (ESI) M/z 376.0[ M + H ]]⁺.

To a solution of 4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) methyl) benzonitrile (130mg,0.346mmol) and di-tert-butyl dicarbonate (0.16mL,0.693mmol) in DCM (4mL) and THF (4mL) at RT was added Raney-Ni (80 mg). The mixture was reacted at RT in H₂Stir for 16h then add MeOH (4mL) and heat the mixtureTo 80 ℃ for 5 hours. After cooling to RT, the suspension was filtered through a pad of celite and the filtrate was concentrated to give the crude product which was purified by silica gel chromatography using DCM/MeOH (50: 1 to 20: 1) to give tert-butyl 4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) methyl) benzylcarbamate (100mg, 60% yield) as a white solid. MS (ESI) M/z380.0[ M + H-100 ]]⁺.

To a solution of tert-butyl 4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) methyl) benzylcarbamate (100mg,0.208mmol) in DCM (4mL) at RT was added TFA (2 mL). The mixture was stirred at RT overnight. The solvent was evaporated to give 3- (4- ((4- (aminomethyl) benzyl) oxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione TFA salt (80mg crude) as a white solid, which was used in the next step without further purification. MS (ESI) M/z380.0[ M + H ]]⁺.

To a solution of tert-butyl 2- ((3- (4- ((4- ((3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenoxy) propyl) amino) acetate (70mg,0.117mmol) in DCM (4mL) at RT was added TFA (1.5mL) and the mixture was stirred at RT overnight. The solvent was evaporated and the residue dissolved in DMF (4mL) followed by addition of 3- (4- ((4- (aminomethyl) benzyl) oxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (80mg,0.162mmol), DIEA (63mg,0.486mmol), HOBt (33mg,0.243mmol) and EDAC & HCl (47mg,0.243 mmol). The mixture was stirred at RT for 18 h. The solvent was evaporated and the crude product was purified by prep-HPLC as described before to give compound 17 as a white solid (11.3mg, 10% yield). MS (ESI) M/z 904.3[ M + H ]]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.98(s,1H),8.79(s,1H),8.54(s,1H),8.32(t,J＝6.0Hz,1H),8.15(s,2H),7.89(s,1H),7.58-7.40(m,9H),7.32-7.26(m,4H),6.78(d,J＝8.8Hz,2H),5.19(s,2H),5.12-5.07(m,1H),4.41-4.21(m,4H),3.96(t,J＝6.4Hz,2H),3.16(s,2H),2.93-2.86(m,1H),2.65-2.62(m,2H),2.59-2.51(m,1H),2.46-2.41(m,1H),2.11(s,3H),2.09-1.95(m,1H),1.90-1.80(m,2H),1.12(s,9H).

Example 18

Compound 18: (S) -3- (6-fluoro-4- { [ p- ({3- [3- (p-fluoro-))- { 5-methyl-4- [ m- (tert-butylaminosulfonyl) amino Radical) phenylamino]-2-pyrimidinylamino } phenoxy) propyl]Ureido } methyl) phenyl]Methoxy } -2-isoindolinyl) - 2, 6-piperidinedione

To a solution of methyl 5-fluoro-3-hydroxy-2-methylbenzoate (3.2g,17.4mmol) and imidazole (2.9g,43.5mmol) in DMF (6mL) at RT was added tert-butyldimethylchlorosilane (3.1g,20.8 mmol). Stirring the mixture at 60 deg.C for 1hr, cooling to RT and extracting with tert-butyl methyl ether, and extracting with anhydrous Na₂SO₄Drying and concentration gave methyl 3- ((tert-butyldimethylsilyl) oxy) -5-fluoro-2-methylbenzoate (5.2g crude) as a yellow oil which was used in the next step without further purification.

To a solution of methyl 3- ((tert-butyldimethylsilyl) oxy) -5-fluoro-2-methylbenzoate (3.2g,10.7mmol) in carbon tetrachloride (30mL) was added NBS (2.9g,16.1mmol) and 2,2' -azobis (2-methylpropanenitrile) (700mg,4.3mmol) at RT. The mixture was stirred at 80 ℃ for 6 h. The solvent was evaporated to give the crude product, which was purified by silica gel chromatography (petroleum ether/EtOAc, 10: 1) to give methyl 2- (bromomethyl) -3- ((tert-butyldimethylsilyl) oxy) -5-fluorobenzoate (4.0g, quantitative yield).

To a solution of methyl 2- (bromomethyl) -3- ((tert-butyldimethylsilyl) oxy) -5-fluorobenzoate (1.0g,2.66mmol) and TEA (0.7mL,5.32mmol) in DMF (6mL) at RT was added 4mL of DMF containing tert-butyl (S) -4, 5-diamino-5-oxopentanoate (696mg,2.92 mmol). The mixture was stirred for 2 hours and then heated to 80 ℃ overnight. Evaporation of the solvent gave a crude product which was purified by silica gel chromatography (DCM/MeOH, 50: 1 to 20: 1) to give (S) -5-amino-4- (6-fluoro-4-hydroxy-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (1.0g of crude product) as a white solid. MS (ESI) M/z 297.0[ M + H-56 ]]⁺.

To (S) -tert-butyl 5-amino-4- (6-fluoro-4-hydroxy-1-oxoisoindolin-2-yl) -5-oxopentanoate (500mg,1.42mmol), 4- (hydroxymethyl) benzonitrile (283mg,2.13mmol) at RT) And triphenylphosphine (930mg,3.55mmol) in THF (4mL) was added DEAD (617mg,3.55 mmol). The mixture was stirred at RT for 2 hours. The solvent was evaporated and the residue was purified by silica gel chromatography (DCM/MeOH, 100: 1 to 50: 1) to give tert-butyl (S) -5-amino-4- (4- ((4-cyanobenzyl) oxy) -6-fluoro-1-oxoisoindolin-2-yl) -5-oxopentanoate (350mg, 52% yield) as a yellow solid. MS (ESI) M/z 412.0[ M + H-56 ]]⁺.

To a solution of (S) -5-amino-4- (4- ((4-cyanobenzyl) oxy) -6-fluoro-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (350mg,0.75mmol) in DCM (4mL) at RT was added TFA (4 mL). The mixture was stirred at RT overnight. The solvent was evaporated to give (S) -5-amino-4- (4- ((4-cyanobenzyl) oxy) -6-fluoro-1-oxoisoindolin-2-yl) -5-oxopentanoic acid (400mg crude) as a yellow solid, which was used in the next step without further purification. MS (ESI) M/z 412.0[ M + H ]]⁺.

To a solution of (S) -5-amino-4- (4- ((4-cyanobenzyl) oxy) -6-fluoro-1-oxoisoindolin-2-yl) -5-oxopentanoic acid (400mg,0.75mmol) in ACN (10mL) at RT was added CDI (485mg,2.99 mmol). The mixture was stirred at 95 ℃ for 3.5 hours. The solvent was evaporated to give the crude product, which was purified by silica gel chromatography (DCM/MeOH, 100: 1 to 50: 1) to give (S) -4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-4-yl) oxy) methyl) benzonitrile (200mg 68%) as a white solid. MS (ESI) M/z394.0[ M + H ]]⁺.

To a solution of (S) -4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-4-yl) oxy) methyl) benzonitrile (200mg,0.51mmol) and di-tert-butyl dicarbonate (166mg,0.76mmol) in THF (6mL) at RT was added Raney-Ni (80 mg). Mixing the mixture in H₂Stirring was continued overnight. The suspension was filtered, the filtrate concentrated and purified by silica gel chromatography (DCM/MeOH, 100: 1 to 20: 1) to give tert-butyl (S) -4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-4-yl) oxy) methyl) benzylcarbamate (90mg, 35% yield) as a white solid. MS (ESI) M/z 398.0[ M + H-100 ]]⁺.

To (S) -4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-4-yl) oxy) methyl) at RTTo a solution of tert-butyl benzylcarbamate (70mg,0.146mmol) in DCM (2mL) was added TFA (0.5mL). The mixture was stirred at RT for 2 hours. The solvent was evaporated to give (S) -3- (4- ((4- (aminomethyl) benzyl) oxy) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (80mg crude) as a white solid, which was used in the next step without further purification. MS (ESI) M/z 398.0[ M + H ]]⁺.

To a solution of (S) -3- (4- ((4- (aminomethyl) benzyl) oxy) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (80mg,0.146mmol) and TEA (45mg,0.438mmol) in THF at RT was added 4-nitrophenyl (3- (4- ((4- ((3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenoxy) propyl) carbamate (90mg,0.138 mmol). After stirring for 15min, TEA (103mg,1.022mmol) was added and the reaction stirred for 2 hr. Evaporation of the solvent afforded the crude product, which was purified by prep-HPLC as previously described to afford compound 18 as a white solid (60.9mg, 46% yield). MS (ESI) M/z908.3[ M + H ]]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.96(s,1H),8.76(s,1H),8.52(s,1H),8.14-8.12(m,2H),7.88(s,1H),7.55-7.40(m,7H),7.26-7.24(m,3H),7.11-7.08(m,1H),6.79(d,J＝8.8Hz,2H),6.36(t,J＝5.6Hz,1H),6.04(t,J＝5.6Hz,1H),5.20(s,2H),5.11-5.06(m,1H),4.36(d,J＝17.2Hz,1H),4.23-4.19(m,3H),3.91(t,J＝6.0Hz,2H),3.19-3.14(m,2H),2.89-2.82(m,1H),2.58-2.50(m,1H),2.45-2.40(m,1H),2.11(s,3H),1.99-1.89(m,1H),1.82-1.79(m,2H),1.12(s,9H).

Example 19

Compound 19: 2- [ (S) -2, 7-dioxo-3-azepanyl]-4- { [ p- (morpholinomethyl) phenyl]First of all Oxy } -1-oxo-5-isoindoline carbonitrile

To a solution of 3-hydroxy-2-methylbenzoic acid (100.0g,660mmol) in anhydrous MeOH (700mL) at 0 deg.C was added thionyl chloride (156.0g,1316 mmol). The reaction was heated to 70 ℃ and continued for 3 hours. The reaction was cooled to RT and the solvent was evaporated. The residue was diluted with water and extracted with EtOAc. Work-up and purification with 0% to 8% EtOAc/petroleum ether gave methyl 3-hydroxy-2-methylbenzoate (102g, 93% yield) as a white solid.

NBS (53.6g,301.2mmol) was added to a solution of methyl 3-hydroxy-2-methylbenzoate (50.0g,301.2mmol) in DCM (800mL) at-78 ℃. The mixture was stirred at-78 ℃ for 1 hour and then concentrated. The crude product was purified by silica gel chromatography, eluting with EtOAc/petroleum ether (0% to 8%) to give methyl 4-bromo-3-hydroxy-2-methylbenzoate (15.0g, 21% yield) as a colorless solid.

To a solution of methyl 4-bromo-3-hydroxy-2-methylbenzoate (10.0g,40.82mmol) in DMF (50mL) was added zinc cyanide (480mg,40.82mmol) and tetrakis (triphenylphosphine) palladium (240mg,2.04 mmol). The mixture was heated to 100 ℃ for 5 hours. The reaction was cooled to RT and the solvent was evaporated. The residue was diluted with water and extracted with EtOAc. Work-up and purification using EtOAc/petroleum ether (0% to 15%) gave methyl 4-cyano-3-hydroxy-2-methylbenzoate as a white solid (2.1g, 27% yield).

To a solution of methyl 4-cyano-3-hydroxy-2-methylbenzoate (2.1g,11.0mmol) and imidazole (1.5g,22.0mmol) in DMF (6mL) at RT was added tert-butyldimethylchlorosilane (1.98g,13.2 mmol). After stirring for 1 hour at 60 ℃, the solution was cooled to RT and extracted with tert-butyl methyl ether over anhydrous Na₂SO₄Dried, filtered and concentrated to give methyl 3- ((tert-butyldimethylsilyl) oxy) -4-cyano-2-methylbenzoate (3.2g crude) as a yellow oil which was used in the next step without further purification.

To a solution of methyl 3- ((tert-butyldimethylsilyl) oxy) -4-cyano-2-methylbenzoate (3.2g,10.5mmol) in carbon tetrachloride (50mL) was added NBS (2.43g,13.64mmol) and 2,2' -azobis (2-methylpropanenitrile) (690mg,4.2mmol) at RT. The suspension was stirred at 80 ℃ for 5 hours. Evaporation of the solvent gave the crude product which was purified by silica gel chromatography (petroleum ether/EtOAc, 10: 1) to give methyl 2- (bromomethyl) -3- (((tert-butyldimethylsilyl) oxy) -4-cyanobenzoate (3.5g 87%) as a colorless oil.

To a solution of methyl 2- (bromomethyl) -3- ((tert-butyldimethylsilyl) oxy) -4-cyanobenzoate (2.65g,6.92mmol) and TEA (1.39g,113.8mmol) in DMF (20mL) at RT was added (S) -3-amino azepan-2-one (1.06g,8.3 mmol). The mixture was stirred for 2 hours, then heated to 50 ℃ and left overnight. After cooling to RT tetrabutylammonium fluoride (2.61g,8.3mmol)) was added. The mixture was heated to 50 ℃ for 1 hour. The solvent was evaporated to give the crude product which was purified by silica gel chromatography (DCM/MeOH, 50: 1 to 20: 1) to give (S) -4-hydroxy-1-oxo-2- (2-oxoazepan-3-yl) isoindoline-5-carbonitrile (1.3g, crude) as a yellow solid.

To a solution of (S) -4-hydroxy-1-oxo-2- (2-oxoazepan-3-yl) isoindoline-5-carbonitrile (1.0g,3.5mmol), 4- (bromomethyl) benzaldehyde (900mg,4.6mmol) in DMF (515mL) was added K₂CO₃(970mg,7.1 mmol). The mixture was heated to 50 ℃ for 2 h. Evaporation of the solvent gave the crude product which was purified by silica gel chromatography (DCM/MeOH, 50: 1 to 20: 1) to give (S) -4- ((4-formylbenzyl) oxy) -1-oxo-2- (2-oxoazepan-3-yl) isoindoline-5-carbonitrile as a yellow solid (600mg, 42% yield). MS (ESI) M/z404.2[ M + H ]]⁺.

To a solution of (S) -4- ((4-formylbenzyl) oxy) -1-oxo-2- (2-oxoazepan-3-yl) isoindoline-5-carbonitrile (980mg,2.44mmol) in ACN/DMSO (12mL/2mL) at RT was added Dess-Martin periodinane (2.6g,6.1 mmol). The mixture was stirred at 80 ℃ overnight. The mixture was cooled to RT and 100mL of saturated sodium thiosulfate solution was added, followed by stirring for 5 min. The mixture was extracted with DCM. Using DCM/ACN, 5:1 to 3: 1 to afford (S) -2- (2, 7-dioxoazepan-3-yl) -4- ((4-formylbenzyl) oxy) -1-oxoisoindoline-5-carbonitrile (600mg, 59% yield) as a white solid. MS (ESI) M/z 418.0[ M + H ]]⁺.

To a solution of (S) -2- (2, 7-dioxoazepan-3-yl) -4- ((4-formylbenzyl) oxy) -1-oxoisoindoline-5-carbonitrile (700mg,1.68mmol) and morpholine (292mg,3.36mmol) in DCM (15mL) at RT was added sodium triacetoxyborohydride (850mg,4.2 mmol). The mixture was stirred for 3 hours and then concentrated. The residue was purified by silica gel chromatography (DCM/ACN, 3: 1 to 1:1)To give compound 19(800mg, 57% yield) as a white solid MS (ESI) M/z 489.2[ M + H ]]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.79(s,1H),7.91(d,J＝7.6Hz,1H),7.54-7.46(m,3H),7.36(d,J＝8.4Hz,2H),5.47(s,2H),5.29-5.25(m,1H),4.86(t,J＝2.4Hz,2H),3.58-3.56(m,4H),3.47(s,2H),3.14-3.06(m,1H),2.58(d,J＝16.4Hz,,1H),2.40-2.34(m,5H),2.13-2.00(m,2H),1.83-1.81(m,1H).

Example 20

Compound 20: (S) -3- (4- { [ p- ({3- [3- (p- { 5-methyl-4- [ m- (tert-butylaminosulfonyl) benzene) Radical amino]-2-pyrimidinylamino } phenoxy) propyl]Ureido } methyl) phenyl]Methoxy } -2-isoindolinyl) -2,6- Piperidinones

To a solution of tert-butyl (S) -4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) methyl) benzylcarbamate (100mg,0.2mmol) in DCM (4mL) at RT was added TFA (1 mL). The mixture was stirred for 1 hour, then the solvent was evaporated to give (S) -3- (4- ((4- (aminomethyl) benzyl) oxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione TFA salt, which was used in the next step without further purification. MS (ESI) M/z380.0[ M + H ]]⁺.

To a solution of (S) -3- (4- ((4- (aminomethyl) benzyl) oxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione TFA salt (0.2mmol) in DCM (4mL) at RT was added TEA (41mg,0.4mmol) and 4-nitrophenyl chloroformate (50mg,0.24 mmol). After stirring for 2 hours, the mixture was concentrated to give (S) -4-nitrophenyl 4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) methyl) benzyl carbamate, which was used in the next step.

To a solution of tert-butyl (3- (4- ((4- ((3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenoxy) propyl) carbamate (120mg,0.2mmol) in DCM (2mL) was added TFA (1 mL). The mixture was stirred at RT for 1 hour, then the solvent was evaporated to give 3- ((2- ((4- (3-aminopropoxy) phenyl) amino) -5-methylpyrimidinePyridin-4-yl) amino) -N- (tert-butyl) benzenesulfonamide, which was used in the next step. MS (ESI) M/z 485.1[ M + H ]]⁺.

To a solution of phenyl (S) -4-nitrophenyl 4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) oxy) methyl) benzylcarbamate (0.2mmol) in THF (4mL) was added TEA (0.2mL), followed by DCM (4mL) containing 3- ((2- ((4- (3-aminopropoxy) phenyl) amino) -5-methylpyrimidin-4-yl) amino) -N- (tert-butyl) benzenesulfonamide (0.2mmol), and the mixture was stirred at RT overnight. The solvent was evaporated and the residue was purified by silica gel chromatography (DCM/MeOH, 10: 1) and prep-HPLC as described before to give compound 20 as a white solid (11.5mg, 6.5% yield)]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.94(s,1H),8.76(s,1H),8.52(s,1H),8.11-8.14(m,2H),7.89(s,1H),7.39-7.78(m,8H),7.24-7.31(m,4H),6.79(d,J＝8.8Hz,2H),6.35(t,J＝6.0Hz,1H),6.03(t,J＝5.6Hz,1H),5.19(s,2H),5.09(dd,J＝4.8,13.2Hz,1H),4.19-4.41(m,4H),3.91(t,J＝6.0Hz,2H),3.16(q,J＝6.4Hz,2H),2.85-2.94(m,1H),2.53-2.58(m,1H),2.42-2.49(m,1H),2.11(s,3H),1.95-1.99(m,1H),1.77-1.84(m,2H),1.12(s,9H).

Example 21

Compound 21: (S) -3- (6-fluoro-4- { [ p- ({2- [3- (p- { 5-methyl-4- [ m- (tert-butylsulfonylamino) amino) Radical) phenylamino]-2-pyrimidinylamino } phenoxy) propylamino]Acetylamino } methyl) phenyl]Methoxy } -2-isoindole Indole-acyl) -2, 7-azacycloheptanediones

To a solution of (S) -3-aminoazepan-2-one (2.0g,15.9mmol) and TEA (2.8mL,19.9mmol) in DMF (30mL) at RT was added methyl 2- (bromomethyl) -3- ((tert-butyldimethylsilyl) oxy) -5-fluorobenzoate (5.0g,13.3mmol) in 10mL of DMF. The mixture was stirred for 2 hours, heated to 50 ℃ and overnight, and cooled to RT. TBAF (2.4g,9.31mmol) was added and the mixture was heated to 70 ℃ for 1 hr. The solvent was evaporated and chromatographed on silica gel (DCM/MeOH, 100: 1 to 30: 1)) The residue was purified to give (S) -6-fluoro-4-hydroxy-2- (2-oxoazepan-3-yl) isoindolin-1-one (3.1g, 83% yield) as a yellow solid. MS (ESI) M/z 279.0[ M + H ]]⁺.

To a solution of (S) -6-fluoro-4-hydroxy-2- (2-oxoazepan-3-yl) isoindolin-1-one (320mg,1.15mmol), tert-butyl 4- (hydroxymethyl) benzylcarbamate (409mg,1.72mmol) and triphenylphosphine (602mg,2.30mmol) in THF (2mL) at RT was added DEAD (400mg,2.30mmol) and the mixture was stirred for 30 min. The solvent was evaporated and the residue was purified by silica gel chromatography (DCM/MeOH, 100: 1 to 30: 1) to give tert-butyl (S) -4- (((6-fluoro-1-oxo-2- (2-oxoazepan-3-yl) isoindolin-4-yl) oxy) methyl) benzylcarbamate (430mg, 75% yield) as a yellow solid. MS (ESI) M/z 398.1[ M + H-100 ]]⁺.

To a solution of tert-butyl (S) -4- (((6-fluoro-1-oxo-2- (2-oxoazepan-3-yl) isoindolin-4-yl) oxy) methyl) benzylcarbamate (200mg,0.40mmol) in ACN/DMSO (4mL/1mL) at RT was added Dess-Martin periodinane (426mg,1.00 mmol). The mixture was stirred at 80 ℃ overnight. After cooling to RT, 20mL of saturated sodium thiosulfate solution were added and the mixture was extracted with DCM. Work-up afforded the crude product, which was washed with tert-butyl methyl ether to give tert-butyl (S) -4- (((2- (2, 7-dioxoazepan-3-yl) -6-fluoro-1-oxoisoindolin-4-yl) oxy) methyl) benzylcarbamate as a white solid (100mg, 50% yield). MS (ESI) M/z 412.0[ M + H-100 ]]⁺.

To a solution of tert-butyl (S) -4- (((2- (2, 7-dioxoazepan-3-yl) -6-fluoro-1-oxoisoindolin-4-yl) oxy) methyl) benzylcarbamate (61mg,0.117mmol) in DCM (4mL) at RT was added TFA (1 mL). The reaction was stirred at RT for 1 hour. Evaporation of the solvent gave the amine TFA salt as a yellow gum.

The amine TFA salt was dissolved in DMA (1mL) and 2- ((3- (4- ((4- ((3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenoxy) propyl) amino) acetic acid (76mg,0.141mmol) was added followed by HOBt (23.7mg,0.176mmol), EDAC & HCl (34.1mg,0.176mmol) and DIEA (30.0mg,0.234 mmol). The reaction was stirred at RT for 10 hours. The solvent is evaporated and the mixture is evaporated,and the residue was purified by prep-HPLC as described previously to give compound 21 as a white solid (10.8mg, 10.2% yield). ms (esi) M/z 936.4[ M + H]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.69(s,1H),8.75(s,1H),8.51(s,1H),8.29(t,J＝6.0Hz,1H),8.14-8.11(m,2H),7.88(s,1H),7.54-7.23(m,10H),7.09-7.07(m,1H),6.77(d,J＝4.8Hz,2H),5.20-5.17(m,3H),4.40(s,2H),4.30(d,J＝6.0Hz,2H),3.96(t,J＝2.4Hz,2H),3.15(s,2H),3.09-3.00(m,1H),2.67-2.54(m,3H),2.32-2.25(m,3H),2.11(s,3H),2.05-1.96(m,2H),1.84-1.71(m,3H),1.12(s,9H).

Example 23

Compound 22: (S) -3- [5- (aminomethyl) -4- { [ p- (morpholinylmethyl) phenyl]Methoxy } -2-isoindole Quinoline acyl radical]-2, 7-azepane dione bistrifluoroacetic acid

To a solution of (S) -2- (2, 7-dioxoazepan-3-yl) -4- ((4- ((morpholinylmethyl) benzyl) oxy) -1-oxoisoindoline-5-carbonitrile (700mg,1.43mmol) and di-tert-butyl dicarbonate (625mg,2.87mmol) in DMF (10mL)/THF (15mL) at RT was added Raney-Ni (500 mg). The mixture was taken at RT in H₂Stirred for 48 hours. The suspension was filtered through a pad of celite and concentrated to give the crude product which was purified by silica gel chromatography (DCM/CAN, 3: 1 to 1:1) to give tert-butyl (S) - ((2- (2, 7-dioxoazepan-3-yl) -4- ((4- (morpholinylmethyl) benzyl) oxy) -1-oxoisoindolin-5-yl) methyl) carbamate (800mg, 85% yield) as a white solid. MS (ESI) M/z593.1[ M + H ]]⁺.

To a solution of tert-butyl (S) - ((2- (2, 7-dioxoazepan-3-yl) -4- ((4- (morpholinylmethyl) benzyl) oxy) -1-oxoisoindolin-5-yl) methyl) carbamate (70mg,0.118mmol) in DCM (3mL) at RT was added TFA (1.0 mL). The mixture was stirred for 1 hour. Evaporation of the solvent afforded compound 22 as a white solid (70mg, 83% yield). MS (ESI) M/z 493.2[ M + H ]]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.75(s,1H),10.56(s,1H),8.29(s,3H),7.64-7.52(m,6H),5.36(s,2H),5.28-5.24(m,1H),4.85-4.73(m,2H),4.39(s,2H),4.14(s,2H),3.97(s,2H),3.65(s,2H),3.24-3.01(m,4H),2.61-2.57(m,2H),2.37-2.32(m,1H),2.15-2.03(m,2H),1.87-1.78(m,1H).

Example 24

Compound 23: (S) -3- [5- ({3- [3- (p- { 5-methyl-4- [ m- (tert-butylaminosulfonyl) phenylamino ] amino Base of]-2-pyrimidinylamino } phenoxy) propyl]Ureido methyl) -4- { [ p- (morpholinylmethyl) phenyl]Methoxy } -2-iso Indolinyl radical]-2, 6-piperidinedione

To a solution of methyl 2- (bromomethyl) -3- ((tert-butyldimethylsilyl) oxy) -4-cyanobenzoate (3.5g,9.096mmol) and TEA (1.84g,18.2mmol) in DMF (15mL) at RT was added tert-butyl (S) -4, 5-diamino-5-oxopentanoate (2.6g,10.91 mmol). The mixture was stirred for 2 hours, then heated to 50 ℃ and left overnight. After cooling to RT tetrabutylammonium fluoride (4.3g,13.6mmol) was added. The mixture was heated to 50 ℃ and held for 1 hour. The solvent was evaporated to give the crude product which was purified by silica gel chromatography (DCM/MeOH, 50: 1 to 20: 1) to give tert-butyl (S) -5-amino-4- (5-cyano-4-hydroxy-1-oxoisoindolin-2-yl) -5-oxopentanoate (1.1g, yield; 34% yield) as a yellow solid.

To a solution of (S) -5-amino-4- (5-cyano-4-hydroxy-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (200mg,0.56mmol), 4- (4- (chloromethyl) benzyl) morpholine (188mg,0.835mmol) in DMF (5mL) was added K₂CO₃(156mg,1.13mmol) and the mixture was heated to 50 ℃ and held for 2 hr. The solvent was evaporated and the residue was purified by silica gel chromatography (DCM/MeOH, 50: 1 to 20: 1) to give tert-butyl (S) -5-amino-4- (5-cyano-4- ((4- (morpholinylmethyl) benzyl) oxy) -1-oxoisoindolin-2-yl) -5-oxopentanoate (240mg, 80% yield) as a yellow solid.

To a solution of tert-butyl (S) -5-amino-4- (5-cyano-4- ((4- (morpholinylmethyl) benzyl) oxy) -1-oxoisoindolin-2-yl) -5-oxopentanoate (240mg,0.44mmol) in DCM (5mL) at RT was added TFA (2 mL). The mixture was stirred overnight and concentrated to give (S) -5-amino-4- (5-cyano-4- ((4- (morpholinylmethyl) benzyl) oxy) -1-oxoisoindolin-2-yl) -5-oxopentanoic acid (200mg, crude) as a yellow oil which was used in the next step without further purification.

To a solution of (S) -5-amino-4- (5-cyano-4- ((4- (morpholinylmethyl) benzyl) oxy) -1-oxoisoindolin-2-yl) -5-oxopentanoic acid (200mg,0.41mmol) in ACN (10mL) at RT was added CDI (200mg,1.22 mmol). The mixture was heated to 50 ℃ for 2 hours. The solvent was evaporated and the residue was purified by silica gel chromatography (DCM/MeOH, 50: 1 to 10: 1) to give (S) -2- (2, 6-dioxopiperidin-3-yl) -4- ((4- (morpholinylmethyl) benzyl) oxy) -1-oxoisoindoline-5-carbonitrile (100mg, 52% yield) as a white solid. MS (ESI) M/z 475.2[ M + H ]]⁺.¹HNMR(400MHz,DMSO-d₆)δ11.05(s,1H),7.92(d,J＝7.6Hz,1H),7.54(d,J＝8Hz,1H),7.47(d,J＝8Hz,2H),7.36(d,J＝8Hz,2H),5.45(s,2H),5.18-5.14(m,1H),4.85-4.66(m,2H),3.58-3.56(m,4H),3.47(s,2H),2.96-2.89(m,1H),2.65-2.60(m,1H),2.47-2.44(m,1H),2.36-2.33(m,4H),2.05-1.99(m,1H).

To a solution of (S) -2- (2, 6-dioxopiperidin-3-yl) -4- ((4- (morpholinylmethyl) benzyl) oxy) -1-oxoisoindoline-5-carbonitrile (600mg,1.265mmol) and di-tert-butyl dicarbonate (550mg,2.53mmol) in DMF (5mL) and MeOH (10mL) at RT was added Raney-Ni (300 mg). The mixture is brought to RT in H₂Stirred for 16 hours. The suspension was filtered through a pad of celite and concentrated to give the crude product which was purified by silica gel chromatography (DCM/MeOH, 50: 1 to 20: 1) to give tert-butyl (S) - ((2- (2, 6-dioxopiperidin-3-yl) -4- ((4- (morpholinylmethyl) benzyl) oxy) -1-oxoisoindolin-5-yl) methyl) carbamate as a white solid (400mg, 55% yield). MS (ESI) M/z 579.1[ M + H ]]⁺.

To a solution of tert-butyl (S) - ((2- (2, 6-dioxopiperidin-3-yl) -4- ((4- (morpholinylmethyl) benzyl) oxy) -1-oxoisoindolin-5-yl) methyl) carbamate (250mg,0.435mmol) in DCM (4mL) at RT was added TFA (1.0 mL). The mixture was stirred at RT for 1 hour. Evaporating the solvent to obtain (S) -3- (5- (amino)Methyl) -4- ((4- (morpholinylmethyl) benzyl) oxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (250mg, 81% yield) as a white solid. MS (ESI) M/z 479.2[ M + H ]]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.02(s,1H),10.37(s,1H),8.25(s,3H),7.61-7.59(m,3H),7.55-7.53(m,3H),5.32(s,2H),5.17-5.12(m,1H),4.78-4.55(m,2H),4.36(s,2H),4.14(d,J＝4.4Hz,2H),3.91(s,2H),3.71-3.60(m,2H),3.26-3.09(m,4H),2.96-2.91(m,1H),2.66-2.61(m,1H),2.46-2.42(m,1H),2.04-1.99(m,1H).

To a solution of (S) -3- (5- (aminomethyl) -4- ((4- (morpholinylmethyl) benzyl) oxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (150mg,0.21mmol) in formic acid (5mL) at RT was added formaldehyde (1mL, 40%). The mixture was heated to 100 ℃ for 1 hour. The solvent was evaporated and the residue was purified by prep-HPLC as described before to give (S) -3- (5- ((dimethylamino) methyl) -4- ((4- (morpholinylmethyl) benzyl) oxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (80mg, 79% yield) as a white solid. MS (ESI) M/z 507.2[ M + H ]]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.05(s,1H),10.91(s,1H),10.01(s,1H),7.68-7.54(m,6H),5.37(s,2H),5.17-5.06(m,2H),4.85-4.78(m,1H),4.65-4.61(m,1H),4.38(s,4H),3.96(s,2H),3.67(s,2H),3.24-2.92(m,4H),2.83-2.61(m,7H),2.50-2.42(m,1H),2.07-2.01(m,1H).

To a solution of (S) -3- (5- (aminomethyl) -4- ((4- (morpholinylmethyl) benzyl) oxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (80mg,0.112mmol) in THF (5mL) was added TEA (113mg,1.12 mmol). The mixture was stirred at RT for 10min, then 4-nitrophenyl (3- (4- ((4- ((3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenoxy) propyl) carbamate (80mg,0.124mmol) was added, followed by TEA (90mg,0.9 mmol). After stirring at RT for 1h, the mixture was concentrated and the residue was purified by prep-HPLC as described before to give compound 23 as a white solid (40mg, 36% yield). MS (ESI) M/z 989.4[ M + H ]]⁺.¹H NMR(400MHz,DMSO-d₆)δ11.01(s,1H),8.79(s,1H),8.54(s,1H),8.13(s,2H),7.90(s,1H),7.57-7.33(m,11H),6.79(d,J＝8Hz,2H),6.36-6.33(m,1H),6.16-6.13(m,1H),5.16-5.09(m,3H),4.65-4.54(m,2H),4.33(d,J＝4Hz,2H),3.93-3.90(m,2H),3.56(s,4H),3.46(s,2H),3.18-3.15(m,2H),2.97-2.88(m,1H),2.62-2.58(m,1H),2.34(s,4H),2.12(s,3H),2.01-1.92(m,1H),1.89(s,1H),1.82-1.79(m,2H),1.12(s,9H).

Example 25

Compound 24: (S) -3- (4- { [ p- ({2- [3- (p- { 5-methyl-4- [ m- (tert-butylaminosulfonyl) benzene) Radical amino]-2-pyrimidinylamino } phenoxy) propylamino]Acetylamino } methyl) phenyl]Methoxy } -2-isoindoline Acyl) -2, 6-piperidinediones

To a solution of 2- ((3- (4- ((4- ((3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenoxy) propyl) amino) acetic acid (54mg,0.1mmol) and (S) -3- (4- ((4- (aminomethyl) benzyl) oxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (0.1mmol) in DMF (2mL) was added DIEA (26mg,0.2mmol), HOBt (20mg,0.15mmol) and EDAC · HCl (29mg,0.15mmol) at RT and the mixture was stirred overnight. The solvent was evaporated and the residue was purified by preparative-TLC (DCM/MeOH, 10: 1) to give compound 24 as a white solid (6.0mg, 6.7% yield). MS (ESI) M/z 904.3[ M + H ]]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.95(s,1H),8.76(s,1H),8.52(s,1H),8.48(s,1H),8.11-8.14(m,2H),7.89(s,1H),7.40-7.54(m,8H),7.27-7.31(m,4H),6.78(d,J＝9.2Hz,2H),5.20(s,2H),5.09(dd,J＝5.2,13.2Hz,1H),4.21-4.41(m,4H),3.96(t,J＝6.0Hz,2H),2.85-2.94(m,1H),2.76(t,J＝6.0Hz,2H),2.53-2.58(m,1H),2.40-2.45(m,2H),2.11(s,3H),1.95-1.98(m,2H),1.87-1.90(m,2H),1.12(s,9H).

Example 26

Compound 25: (S) -3- (6-fluoro-4- { [ p- ({2- [3- (p- { 5-methyl-4- [ m- (tert-butylaminosulfonyl) amino) Radical) phenylamino]-2-pyrimidinylamino } phenoxy) propylamino]Acetylamino } methyl) phenyl]Methoxy } -2-isoindole Indole-acyl) -2, 6-piperidinedione

To a solution of methyl 5-fluoro-3-hydroxy-2-methylbenzoate (3.2g,17.4mmol) and imidazole (2.9g,43.5mmol) in DMF (6mL) at RT was added tert-butyldimethylchlorosilane (3.1g,20.8 mmol). The mixture was stirred at 60 ℃ for 1 hour, then cooled to RT and extracted with tert-butyl methyl ether. The combined organic layers were passed over anhydrous Na₂SO₄Dried, filtered and concentrated to give methyl 3- ((tert-butyldimethylsilyl) oxy) -5-fluoro-2-methylbenzoate (5.2g crude) as a yellow oil which was used in the next step without further purification.

To a solution of methyl 3- ((tert-butyldimethylsilyl) oxy) -5-fluoro-2-methylbenzoate (3.2g,10.7mmol) in carbon tetrachloride (30mL) was added NBS (2.9g,16.1mmol) and 2,2' -azobis (2-methylpropanenitrile) (700mg,4.3mmol) at RT. The mixture was stirred at 80 ℃ for 6 hours. The solvent was evaporated to give the crude product, which was purified by silica gel chromatography (petroleum ether/EtOAc, 10: 1) to give methyl 2- (bromomethyl) -3- ((tert-butyldimethylsilyl) oxy) -5-fluorobenzoate (4.0g, quantitative yield).

To a solution of methyl 2- (bromomethyl) -3- ((tert-butyldimethylsilyl) oxy) -5-fluorobenzoate (1.0g,2.66mmol) and TEA (0.7mL,5.32mmol) in DMF (6mL) at RT was added 4mL of DMF containing tert-butyl 4, 5-diamino-5-oxopentanoate (696mg,2.92 mmol). The mixture was stirred for 2 hours, then heated to 80 ℃ and left overnight. Evaporation of the solvent gave a crude product which was purified by silica gel chromatography (DCM/MeOH, 50: 1 to 20: 1) to give tert-butyl 5-amino-4- (6-fluoro-4-hydroxy-1-oxoisoindolin-2-yl) -5-oxopentanoate (1.0g crude) as a white solid. MS (ESI) M/z 297.0[ M + H-56 ]]⁺.

To a solution of tert-butyl 5-amino-4- (6-fluoro-4-hydroxy-1-oxoisoindolin-2-yl) -5-oxopentanoate (500mg,1.42mmol), 4- (hydroxymethyl) benzonitrile (283mg,2.13mmol) and triphenylphosphine (930mg,3.55mmol) in THF (4mL) at RT was added DEAD (617mg,3.55 mmol). The mixture was stirred at RT for 2 hours. The solvent was evaporated and the residue was purified by silica gel chromatography (DCM/MeOH, 100: 1 to 50: 1) to give 5-ammonia as a yellow solidTert-butyl yl-4- (4- ((4-cyanobenzyl) oxy) -6-fluoro-1-oxoisoindolin-2-yl) -5-oxopentanoate (350mg, 52% yield). MS (ESI) M/z 412.0[ M + H-56 ]]⁺.

To a solution of tert-butyl 5-amino-4- (4- ((4-cyanobenzyl) oxy) -6-fluoro-1-oxoisoindolin-2-yl) -5-oxopentanoate (350mg,0.75mmol) in DCM (4mL) at RT was added TFA (4 mL). The mixture was stirred at RT overnight. The solvent was evaporated to give 5-amino-4- (4- ((4-cyanobenzyl) oxy) -6-fluoro-1-oxoisoindolin-2-yl) -5-oxopentanoic acid (400mg, crude) as a yellow solid which was used in the next step without further purification. MS (ESI) M/z 412.0[ M + H ]]⁺.

To a solution of 5-amino-4- (4- ((4-cyanobenzyl) oxy) -6-fluoro-1-oxoisoindolin-2-yl) -5-oxopentanoic acid (400mg,0.75mmol) in ACN (10mL) at RT was added CDI (485mg,2.99 mmol). The mixture was stirred at 95 ℃ for 3.5 hours. The solvent was evaporated to give the crude product, which was purified by silica gel chromatography (DCM/MeOH, 100: 1 to 50: 1) to give 4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-4-yl) oxy) methyl) benzonitrile (200mg, 68%) as a white solid. MS (ESI) M/z394.0[ M + H ]]⁺.

To a solution of 4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-4-yl) oxy) methyl) benzonitrile (200mg,0.51mmol) and di-tert-butyl dicarbonate (166mg,0.76mmol) in THF (6mL) at RT was added Raney-Ni (80 mg). At RT in H₂The mixture was stirred overnight. The suspension was filtered through a pad of celite and the filtrate was concentrated to give the crude product which was purified by silica gel chromatography (DCM/MeOH, 100: 1 to 20: 1) to give tert-butyl 4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-4-yl) oxy) methyl) benzylcarbamate (90mg, 35% yield) as a white solid. MS (ESI) M/z 398.0[ M + H-100 ]]⁺.

To a solution of tert-butyl 4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-4-yl) oxy) methyl) benzylcarbamate (80mg,0.161mmol) in DCM (4mL) at RT was added TFA (1 mL). The reaction was stirred for 1 hour. The solvent was evaporated and the residue was dried to give the amine TFA salt as a yellow gum.

The amine TFA salt was dissolved in DMA (1mL) and 2- ((3- (4- ((4- ((3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenoxy) propyl) amino) acetic acid (109mg,0.161mmol) was added followed by HOBt (32.6mg,0.242mmol), EDAC-HCl (46.5mg,0.242mmol) and DIEA (41.5mg,0.322mmol) and the mixture was stirred at RT for 10 h. The solvent was evaporated and the residue was purified by prep-HPLC as described before to give compound 25 as a white solid (23.9mg, 16% yield). MS (ESI) M/z 922.3[ M + H ]]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.96(s,1H),8.75(s,1H),8.52(s,1H),8.29(t,J＝6.4Hz,1H),8.14-8.11(m,2H),7.88(s,1H),7.55-7.23(m,10H),7.10-7.08(m,1H),6.77(d,J＝5.2Hz,2H),5.19(s,2H),5.08(dd,J＝8.4,13.6Hz,1H),4.37-4.18(m,4H),3.95(t,J＝6.4Hz,1H),3.16(s,2H),2.93-2.83(m,1H),2.66-2.57(m,3H),2.11(s,3H),2.02-1.93(m,1H),1.86-1.79(m,3H),1.12(s,9H).

Example 27

Compound 26: (S) -3- (4- {2- [ p- (morpholinylmethyl) phenyl)]Ethoxy } -2-isoindolinoyl) -2, 7-azacycloheptanediones

Lithium aluminum hydride (1M in THF, 36mL) was added dropwise to a solution of methyl 4- (2-methoxy-2-oxoethyl) benzoate (5g,0.24mol) in THF (25mL) at 0 deg.C. The mixture was stirred at 0 ℃ for 2 hours and then Na was added₂SO₄The reaction was quenched with decahydrate, diluted with EtOAc and filtered. The filtrate was washed with brine and dried over anhydrous Na₂SO₄Drying, filtration and concentration gave 2- (4- (hydroxymethyl) phenyl) ethanol (3g, crude) as a yellow oil.¹H NMR(400MHz,DMSO-d₆)δ7.13-7.23(m,4H),5.08(t,J＝5.6Hz,1H),4.61(t,J＝5.2,8.4Hz,1H),4.44(d,J＝7.0Hz,2H),3.54-3.59(m,2H),2.69(t,J＝7.2Hz,2H).

To a stirred solution of 2- (4- (hydroxymethyl) phenyl) ethanol (3g, crude, 19.7mmol) in chloroform (30mL) was added manganese dioxide (6.9g,79 mmol). The mixture was stirred at 70 ℃ overnight and then filteredFiltered and concentrated. The residue was purified by silica gel chromatography (petrol/EtOAc, 5: 1) to give 4- (2-hydroxyethyl) benzaldehyde (1.3g, 38% after 2 steps) as a yellow oil.¹H NMR(300MHz,CDCl₃)δ9.90(s,1H),7.76(d,J＝8.0Hz,2H),7.34(d,J＝8.0Hz,2H),3.84(t,J＝6.4Hz,2H),2.88(t,J＝6.4Hz,2H).

To a stirred solution of 4- (2-hydroxyethyl) benzaldehyde (1.3g,8.67mmol) in DCM (20mL) was added tosyl chloride (2.5g,13mmol) and TEA (4.8 mL). The mixture was stirred at RT overnight, then evaporated and purified by silica gel chromatography (petrol/EtOAc, 5: 1) to give 4-formylphenethyl 4-methylbenzenesulfonate (2g, 77% yield) as a white solid.

To a stirred solution of (S) -4-hydroxy-2- (2-oxoazepan-3-yl) isoindolin-1-one (250mg,0.96mmol) and 4-formylphenethyl 4-methylbenzenesulfonate (392mg,1.15mmol) in ACN (5mL) at RT was added K₂CO₃(400mg,2.88 mmol). After stirring at 80 ℃ overnight, the mixture was concentrated and the residue was purified by silica gel chromatography (DCM/MeOH, 50: 1) to give (S) -4- (2- ((1-oxo-2- (2-oxoazepan-3-yl) isoindolin-4-yl) oxy) ethyl) benzaldehyde (100mg, 27% yield) as a colorless oil. MS (ESI) M/z 393.1[ M + H ]]⁺.

Dess-Martin reagent (530mg,1.25mol) was added to a solution of (S) -4- (2- ((1-oxo-2- (2-oxoazepan-3-yl) isoindolin-4-yl) oxy) ethyl) benzaldehyde (100mg,0.25mmol) in 1, 2-dichloroethane (6mL) and DMSO (1mL) at RT. The mixture was stirred at 80 ℃ overnight, then cooled to RT and filtered. The filtrate was quenched with saturated sodium thiosulfate solution and extracted with DCM. Work-up and purification by preparative-TLC (EtOAc) gave (S) -4- (2- ((2- (2, 7-dioxoazepan-3-yl) -1-oxoisoindolin-4-yl) oxy) ethyl) benzaldehyde (40mg, 38% yield) as a white solid. MS (ESI) M/z 407.0[ M + H ]]⁺.

To a solution of (S) -4- (2- ((2- (2, 7-dioxoazepan-3-yl) -1-oxoisoindolin-4-yl) oxy) ethyl) benzaldehyde (40mg,0.1mmol) and morpholine (26mg,0.3mmol) in DCM (5mL) at RT was added sodium triacetoxyborohydride (106mg,0.5 mmol).The mixture was stirred overnight and then concentrated. The residue was purified by prep-HPLC as described previously to give compound 26 as a white solid (18mg, 38% yield). MS (ESI) M/z 478.1[ M + H ]]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.72(s,1H),7.45(t,J＝8.0Hz,1H),7.23-7.30(m,6H),5.22(dd,J＝4.8,12.4Hz,1H),4.36(s,2H),4.32(t,J＝6.8Hz,2H),3.55(t,J＝4.4Hz,4H),3.41(s,2H),3.03-3.08(m,3H),2.59-2.60(m,1H),2.29-2.32(m,5H),1.99-2.10(m,2H),1.74-1.84(m,1H).

Example 28

Compound 27: (S) -3- [5- ({3- [3- (p- { 5-methyl-4- [ m- (tert-butylaminosulfonyl) phenylamino ] amino Base of]-2-pyrimidinylamino } phenoxy) propyl]Ureido methyl) -4- { [ p- (morpholinylmethyl) phenyl]Methoxy } -2-iso Indolinyl radical]-2, 7-azacycloheptanedione

To a solution of (S) -3- (5- (aminomethyl) -4- ((4- (morpholinomethyl) benzyl) oxy) -1-oxoisoindolin-2-yl) azepan-2, 7-dione (50mg,0.084mmol) in THF (5mL) at RT was added TEA (68mg,0.672mmol) followed by a suspension of 4-nitrophenyl (3- (4- ((4- ((3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenoxy) propyl) carbamate (54mg,0.084mmol) in THF (1 mL). The mixture was stirred for 3 hours. The solvent was evaporated and the residue was purified by silica gel chromatography, eluting with DCM/MeOH (0% to 10%) to give the crude product as a white gum (70mg), which was further purified by prep-HPLC as described previously to give compound 27 as a white solid (27.7mg, 33% yield)]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.70(s,1H),8.76(s,1H),8.53(s,1H),8.13(s,1H),7.90(s,1H),7.59-7.38(m,9H),7.34(d,J＝8.0Hz,2H),6.79(d,J＝8.8Hz,2H),6.34(t,J＝6.0Hz,1H),6.13(t,J＝5.6Hz,1H),5.23(dd,J＝4.8,12.0Hz,1H),5.18(s,2H),4.65(s,2H),4.33(d,J＝5.2Hz,2H),3.92(t,J＝6.0Hz,2H),3.58-3.55(m,4H),3.47(s,2H),3.20-3.15(m,2H),3.12-3.04(m,1H),2.60-2.56(m,1H),2.35-2.31(m,5H),2.12(s,3H),2.08-1.99(m,1H),1.86-1.78(m,4H),1.12(s,9H).

PBMC assay

Frozen Primary Blood Mononuclear Cells (PBMCs) were purchased from AllCells. Cells were thawed quickly and washed once with RPMI-1640/10% FBS.

Cells were pretreated with DMSO or Compound 1 alone for 1 hour, then induced with 100ng/mL Lipopolysaccharide (LPS) for 18-24 hours according to the manufacturer's protocol, IL-1 β, IL-6 and TNF α in the supernatant were analyzed using the Meso Scale assay, negative control wells were treated with DMSO.

For IL-2 analysis, a 96-well plate was pre-coated with 1. mu.g/mL anti-human CD3 antibody (OKT3, eBioscience Inc.). After washing with PBS, compound 1(50 μ L/well) was added followed by PBMC diluted at 3-4 million cells/mL (150 μ L/well). Plates were incubated for 24 hours and supernatants were collected for mesoscale el-2 analysis.

The activity of the compound was measured as fold difference from the DMSO control IL-1 β activity is shown in figure 1, IL-6 activity is shown in figure 2, TNF α activity is shown in figure 3, IL-2 activity is shown in figure 4.10 μ M additional data for the compound (shown as percent inhibition) is shown in table 1,1 μ M additional data for the compound is shown in table 2, and 0.1 μ M additional data for the compound is shown in table 3 additional data for IL-activity (measured as fold change in activity) is shown in tables 4-6.

TABLE 1

TABLE 2

TABLE 3

TABLE 4

TABLE 5

TABLE 6

Western blot analysis

Western blot protocol: jurkat cells were grown in RPMI 1640 supplemented with streptomycin, penicillin and 10% fetal bovine serum.

At about 10⁶cells/mL Jurkat cells were cultured, DMSO or the indicated compound at the indicated concentration was added to the cells, and allowed to incubate for the indicated time. Whole cell extracts were prepared using RIPA reagent according to the manufacturer's protocol (Pierce). Briefly, wash in PBS-5X 10⁶Once per cell, the cell pellet was resuspended in RIPA solution and allowed to incubate for 10min at room temperature. Cell debris was removed by centrifugation and the cleared whole cell lysate was transferred to a new tube for further analysis.

For western blot analysis, whole cell extracts were separated on 4-12% SDS-polyacrylamide gels, transferred to nitrocellulose and probed with the indicated primary antibody. The membrane was then washed and probed with a suitable horseradish peroxidase (HRP) conjugated secondary antibody. Signals were detected using the WesternBright Tianlang red reagent (Advansta). The results are shown in fig. 5A and 5B.

The following antibodies were used in these studies:

β -actin mouse anti-b-actin was obtained from Cell Signaling (8H10D10).

CK1 α goat polyclonal antibody Santa Cruz Biotechnology, sc-6477(Santa Cruz, CA)

Ikaros rabbit monoclonal antibody: cell Signaling, #9034, D10E5(Danver, MA)

Donkey anti-goat IgG-HRP: santa Cruz Biotechnology, sc-2056(Santa Cruz, CA)

Goat anti-rabbit IgG-HRP: cell Signaling, #7074(Danver, MA)

Goat anti-mouse IgG-HRP: sigma, A4416(St. Louis, MO)

Cell viability assay

Molm-13 and MV-4-11 cells were cultured in RPMI-1640 (10% FBS/1% penicillin-streptomycin) and seeded at 20,000 cells/well in white-walled 96-well plates.

Cells were treated with the indicated concentrations of compound or DMSO (control) and cultures were incubated at 37 ℃ and 5% CO₂Incubate for 3 days. After the incubation period, 100. mu.L of CellTiterGlow (CTG) reagent was added to each well

Luminocyte viability assay, Promega (Madison, WI)). After incubation for 10min with shaking, luminescence was measured using a Victor Wallac luminometer.

The proliferation activity of the Molm-13 cells is shown in tables 7 to 9. MV-4-11 cell proliferation activity is shown in tables 10 and 11.

TABLE 7

TABLE 8

TABLE 9

Watch 10

TABLE 11

While the application has been illustrated and described in detail in the drawings and foregoing description, such illustration and description are to be considered illustrative or exemplary and not restrictive. The present application is not limited to the disclosed embodiments. Variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed disclosure, from a study of the drawings, the disclosure, and the appended claims.

All references cited herein are incorporated by reference herein in their entirety. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material.

Unless otherwise defined, all terms (including technical and scientific terms) are to be given their ordinary and customary meaning to those of ordinary skill in the art, and are not to be limited to specific or custom meanings unless expressly so defined herein. It should be noted that the use of particular terminology when describing certain features or aspects of the application should not be taken to imply that the terminology is being redefined herein to be restricted to including any specific characteristics of the features or aspects of the application with which that terminology is associated.

Where numerical ranges are provided, it is understood that the upper and lower limits of the ranges and each value between the upper and lower limits are included in the embodiments.

Terms and phrases used in this application, and variations thereof, especially in the appended claims, should be construed as open ended as opposed to limiting unless expressly stated otherwise. As examples of the foregoing, the term "including" should be read to mean "including, but not limited to," "including but not limited to," and the like; the term "comprising" as used herein is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional unrecited elements or method steps; the term "having" should be read as "having at least"; the term "including" should be read as "including but not limited to"; the term "example" is used to provide exemplary instances of the items in discussion, rather than an exhaustive or limiting list thereof; adjectives such as "known," "normal," "standard," and terms of similar meaning should not be construed as limiting the item described to a given time period or to an item available as of a given time, but rather should be read to encompass normal or standard technologies that may be available or known now or at any time in the future; and the use of terms such as "preferably," "preferred," "desired," or "desirable" and words of similar import should not be construed as indicating any critical, required, or essential features of the structure or function of the invention, but merely as providing prominent alternative or additional features that may or may not be utilized in a particular embodiment of the invention. In addition, the term "comprising" should be understood to be the same as the phrase "including at least" or "including at least". When used in the context of a method, the term "comprising" means that the method includes at least the recited steps, but may include additional steps. The term "comprising" when used in the context of a compound or composition means that the compound or composition includes at least the recited features or components, but may also include additional features or components. Also, a group of items linked with the conjunction "and" should not be read as requiring that each and every one of those items be present in the group, but rather should be read as "and/or" unless expressly stated otherwise. Similarly, a group of items linked with the conjunction "or" should not be read as requiring exclusivity among the group, but rather should be read as "and/or" unless expressly stated otherwise.

With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. For clarity reasons, a number of singular/plural permutations may be specifically listed herein. The indefinite article "a" or "an" does not exclude a plurality. A single processor (processor) or other unit may fulfill the functions of several items recited in the claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims (preferencesign) shall not be construed as limiting the scope thereof.

It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases "at least one" and "one or more" to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles "a" or "an" limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases "one or more" or "at least one" and indefinite articles such as "a" or "an" (e.g., "a" and/or "an" should typically be interpreted to mean "at least one" or "one or more" and the use of definite articles to introduce a claim recitation. The direct recitation of "two recitations," without other modifiers, typically means at least two recitations, or two or more recitations). Further, in those instances where a convention analogous to "at least one of A, B and C, etc." is used, in general such a construction is intended to mean that one of ordinary skill in the art would understand the meaning of the convention (e.g., "a system having at least one of A, B and C" would include, but not be limited to, systems that have a alone, B alone, C alone, a and B together, a and C together, B and C together, and/or A, B and C together, etc.). In those instances where a convention analogous to "A, B or at least one of C, etc." is used, in general such a construction is intended that one skilled in the art will understand the meaning of the convention (e.g., "a system having at least one of A, B and C" will include, but not be limited to, systems that have a alone, B alone, C alone, a and B together, a and C together, B and C together, and/or A, B and C together, etc.). It will be further understood by those within the art that virtually any alternative words and/or phrases presenting two or more alternative terms, whether in the specification, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase "a or B" will be understood to include the possibility of "a" or "B" or "a and B".

All numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth herein are approximations that may vary depending upon the desired properties to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of any claims in any application claiming priority to the present application, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.

Claims

1. A compound of the general formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

Q₁is CH₂、O、NR₂S or a bond;

Q₂is CH₂Or a bond;

x is CH₂Or C ═ O;

X₁is hydrogen, deuterium, methyl or fluorine;

ring B is

Wherein Y is₁Is N or CR_3A；Y₂Is N or CR_3B；Y₃Is N or CR_3C；Y₄Is N or CR_3D；Y₅Is N or CR_3E；

Each R₁Independently is deuterium, hydroxy, halogen, nitro, substituted or unsubstituted amino, substituted or unsubstituted C₁-C₆Alkoxy, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₂-C₆Alkenyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted 3 to 10 membered heterocyclyl,Substituted or unsubstituted C₆-C₁₀Aryl, substituted or unsubstituted 5 to 10 membered heteroaryl or L-Y;

R₂is hydrogen, deuterium, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₂-C₆Alkenyl, acyl or- (SO)₂)-C₁-C₆An alkyl group;

each R_3A、R_3B、R_3C、R_3DAnd R_3EIndependently hydrogen, deuterium, hydroxyl, halogen, nitro, substituted or unsubstituted amino, substituted or unsubstituted C₁-C₆Alkoxy, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₂-C₆Alkenyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted 3 to 10 membered heterocyclyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl or L-Y;

m is 0, 1,2 or 3;

n is 1,2 or 3;

l is-Z₁-(R₄)_t-Z₂–；–Z₁-(R₄-O-R₄)_t-Z₂–；–Z₁(R₄-NH-R₄)_t-Z₂–；–Z₁-(R₄-(NHCO)-R₄)_t-Z₂–；–Z₁-(R₄-(NHC(O)NH)-R₄)_t-Z₂-; or-Z₁-(R₄-(CONH)-R₄)_t-Z₂–；

Z₁And Z₂Independently selected from-NH-; -O-; -CH₂–；–NH(CO)–；–(CO)NH–；–CH₂NH–；–NHCH₂–；–(CO)NHCH₂–；–CH₂CH₂NH–；–CH₂NH (CO) -; or-NHCH₂CH₂–；

Each R₄Independently is unsubstituted C₁-C₆An alkylene group;

t is 1,2,3, 4,5 or 6; and

y is

Wherein Y is derivatized to link to L; and

wherein Y is₁、Y₂、Y₃、Y₄And Y₅At least one of which is R respectively_3A、R_3B、R_3C、R_3DOr R_3E；

When Q is₁Is CH₂Or when a bond is present, then R_3A、R_3B、R_3C、R_3DOr R_3EIs not hydrogen;

when R is₁When L-Y is present, R_3A、R_3B、R_3C、R_3DAnd R_3EEach of which is not L-Y; and

when Q is₂Is a bond, Q₁Is a bond or CH₂(ii) a And

when Q is₁Is a bond, X₁Is hydrogen or methyl and Q₂Is CH₂(ii) a Then m is not 0; or

When Q is₁Is a bond, X₁Is hydrogen or methyl and Q₂Is CH₂(ii) a Then R is₁、R_3A、R_3B、R_3C、R_3DAnd R_3EOne of them is L-Y.

2. A compound of the general formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

Q₁is CH₂、O、NR₂S or a bond;

Q₂is CH₂Or a bond;

x is CH₂Or C ═ O;

X₁is hydrogen, deuterium or fluorine;

ring B is

Each R₁Independently is deuterium, hydroxy, halogen, nitro, substituted or unsubstituted amino, substituted or unsubstituted C₁To C₆Haloalkyl, substituted or unsubstituted C₁-C₆Alkoxy, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₂-C₆Alkenyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted 3 to 10 membered heterocyclyl, substituted or unsubstituted C₆-C₁₀Aryl, substituted or unsubstituted 5 to 10 membered heteroaryl or L-Y;

each R_3A、R_3B、R_3C、R_3DAnd R_3EIndependently hydrogen, deuterium, hydroxyl, halogen, nitro, substituted or unsubstituted amino, substituted or unsubstituted C₁To C₆Haloalkyl, substituted or unsubstituted C₁-C₆Alkoxy, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₂-C₆Alkenyl, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted 3 to 10 membered heterocyclyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylAlkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl or L-Y;

m is 0, 1,2 or 3;

n is 1 or 2;

l is-Z₁-(R₄-O-R₄)_t-Z₂–；–Z₁(R₄-NH-R₄)_t-Z₂–；–Z₁-(R₄-(NHCO)-R₄)_t-Z₂-; or-Z₁-(R₄-(CONH)-R₄)_t-Z₂–；

Z₁is-NH-; -O-; -CH₂–；–NH(CO)–；–(CO)NH–；–CH₂NH–；–NHCH₂–；–CH₂NH (CO) -or-NHCH₂CH₂–；

Z₂is-NH-; -O-; -CH₂-; -nh (co) -; or- (CO) NH-; -CH₂NH–；–NHCH₂-; or-NHCH₂CH₂–；

Each R₄Independently is unsubstituted C₁-C₆An alkylene group;

t is 1,2,3, 4,5 or 6; and

y is

Wherein Y is derivatized to link to L; and

wherein Y is₁、Y₂、Y₃、Y₄And Y₅At least one of which is CR₃；

when R is₁Is L-Y, R_3A、R_3B、R_3C、R_3DAnd R_3EEach of which is not L-Y; and

when Q is₁In the case of a key, the key is,then m is not 0.

3. The compound of claim 1 or 2, wherein X is CH₂。

4. A compound according to claim 1 or 2, wherein X is C ═ O.

5. The compound of any one of claims 1-4, wherein X₁Is hydrogen.

6. The compound of any one of claims 1-4, wherein X₁Is fluorine.

7. The compound of any one of claims 1-5, wherein Q₁Is NR₂。

8. The compound of any one of claims 1-7, wherein R₂Is hydrogen.

9. The compound of any one of claims 1-7, wherein R₂Is substituted or unsubstituted C₁-C₆An alkyl group.

10. The compound of any one of claims 1-7, wherein R₂Is unsubstituted C₁-C₆An alkyl group.

11. The compound of any one of claims 1-7, wherein R₂Is an acyl group.

12. The compound of any one of claims 1-7, wherein R₂Is- (SO)₂)-C₁-C₆An alkyl group.

13. The compound of any one of claims 1-7, wherein R₂Is methyl.

14. The compound of any one of claims 1-6, wherein Q₁Is CH₂。

15. The compound of any one of claims 1-6, wherein Q₁Is O.

16. The compound of any one of claims 1-6, wherein Q₁Is S.

17. The compound of any one of claims 1-6, wherein Q₁Is a bond.

18. The compound of any one of claims 1-17, wherein Q₂Is CH₂。

19. The compound of any one of claims 1-17, wherein Q₂Is a bond.

20. The compound of any one of claims 1-19, wherein n is 1.

21. The compound of any one of claims 1-19, wherein n is 2.

22. The compound of any one of claims 1-21, wherein m is 1.

23. The compound of any one of claims 1-21, wherein m is 2.

24. The compound of any one of claims 1-21, wherein m is 3.

25. The compound of any one of claims 1-18 or 20-21, wherein m is 0.

26. The compound of any one of claims 1-25, wherein each R₁Independently is halogen, substituted or unsubstituted amino, substituted or unsubstituted C₁-C₆Alkoxy, substituted or unsubstituted C₃-C₈Cycloalkyl or substituted or unsubstituted C₁-C₆An alkyl group.

27. The compound of any one of claims 1-25, wherein each R₁Independently halogen, substituted or unsubstituted amino, unsubstituted C₁-C₆Haloalkyl, unsubstituted C₁-C₆Alkoxy, unsubstituted C₃-C₈Cycloalkyl or unsubstituted C₁-C₆An alkyl group.

28. The compound of any one of claims 26-27, wherein each R₁Independently of one another, fluorine, chlorine, -NH₂、-NH(CH₃)、-N(CH₃)₂、-CF₃、-OCH₃、-OCH₂CH₃、-OCH(CH₃)₂、-CH₃、-CH₂CH₃、–CH(CH₃)₂Unsubstituted cyclopropyl, unsubstituted cyclobutyl, or unsubstituted cyclopentyl.

29. The compound of any one of claims 1-28, wherein ring B is selected from:

30. the compound of any one of claims 1-29, wherein R_3A、R_3B、R_3C、R_3DAnd R_3EIn (1)Each is independently hydrogen, deuterium, hydroxy, halogen, nitro, substituted or unsubstituted amino, substituted or unsubstituted C₁-C₆Alkoxy, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₂-C₆Alkenyl, substituted or unsubstituted C₃-C₈A cycloalkyl group, a substituted or unsubstituted 3 to 10 membered heterocyclyl group, a substituted or unsubstituted alkoxyalkyl group, a substituted or unsubstituted cycloalkylalkyl group, a substituted or unsubstituted heterocyclylalkyl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted heteroaralkyl group.

31. The compound of any one of claims 1-29, wherein R_3A、R_3B、R_3C、R_3DAnd R_3EEach of which is independently hydrogen, hydroxy, halogen, nitro, unsubstituted amino, unsubstituted C₁-C₆Haloalkyl, unsubstituted C₁-C₆Alkoxy, unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₃-C₈A cycloalkyl group, a substituted or unsubstituted 3 to 10 membered heterocyclyl group, a substituted or unsubstituted alkoxyalkyl group, a substituted or unsubstituted cycloalkylalkyl group, a substituted or unsubstituted heterocyclylalkyl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted heteroaralkyl group.

32. The compound of any one of claims 1-29, wherein R_3A、R_3B、R_3C、R_3DAnd R_3EEach of which is independently hydrogen, hydroxy, halogen, nitro, unsubstituted amino, unsubstituted C₁-C₆Haloalkyl, unsubstituted C₁-C₆Alkoxy, unsubstituted C₁-C₆Alkyl, unsubstituted C₃-C₈Cycloalkyl, unsubstituted 3 to 10 membered heterocyclyl, unsubstituted cycloalkylalkyl, unsubstituted 3 to 10 membered heterocyclylalkyl, unsubstituted aralkyl, or unsubstituted 5 to 10 membered heteroaralkyl.

33. The compound of any one of claims 1-32, wherein R_3A、R_3B、R_3C、R_3DAnd R_3EEach of which is independently hydrogen, halogen, unsubstituted C₁-C₆Haloalkyl, unsubstituted C₁-C₆Alkoxy, unsubstituted C₁-C₆An alkyl group, an unsubstituted 3 to 10 membered heterocyclyl group or an unsubstituted 3 to 10 membered heterocyclylalkyl group.

34. The compound of any one of claims 1-33, wherein R_3A、R_3B、R_3C、R_3DAnd R_3EOne of them is halogen, unsubstituted C₁-C₆Haloalkyl, unsubstituted C₁-C₆Alkoxy, unsubstituted C₁-C₆An alkyl group, an unsubstituted 3 to 10 membered heterocyclyl group or an unsubstituted 3 to 10 membered heterocyclylalkyl group, and R_3A、R_3B、R_3C、R_3DAnd R_3EThe others in (a) are hydrogen.

35. The compound of any one of claims 1-34, wherein R_3A、R_3B、R_3C、R_3DAnd R_3EOne of them is fluorine, chlorine, -CF₃、-OCH₃Unsubstituted C₁-C₆An alkyl group, an unsubstituted 3 to 10 membered heterocyclyl group or an unsubstituted 3 to 10 membered heterocyclylalkyl group, and R_3A、R_3B、R_3C、R_3DAnd R_3EThe other of the groups is hydrogen.

36. The compound of any one of claims 1-33, wherein R_3A、R_3B、R_3C、R_3DAnd R_3EOne of them is

And R is_3A、R_3B、R_3C、R_3DAnd R_3EThe other of the groups is hydrogen.

37. The compound of any one of claims 1-24, wherein one R₁Is L-Y.

38. The compound of any one of claims 1-28, wherein R_3A、R_3B、R_3C、R_3DAnd R_3EOne of them is L-Y.

39. The compound of claim 38, wherein Y₃Is C-L-Y.

40. The compound of any one of claims 1-24 or 37-39, wherein L is-Z₁-(R₄-O-R₄)_t-Z₂–。

41. The compound of any one of claims 1-24 or 37-39, wherein L is-Z₁(R₄-NH-R₄)_t-Z₂–。

42. The compound of any one of claims 1-24 or 37-39, wherein L is Z₁-(R₄-(NHCO)-R₄)_t-Z₂-or-Z₁-(R₄-(NHC(O)NH)-R₄)_t-Z₂–。

43. The compound of any one of claims 1-24 or 37-39, wherein L is-Z₁-(R₄-(CONH)-R₄)_t-Z₂–。

44. The method of any one of claims 1-24 and 40-43A compound wherein Z₁is-NH-.

45. The compound of any one of claims 1-24 and 40-43, wherein Z₁is-O-.

46. The compound of any one of claims 1-24 and 40-43, wherein Z₁is-CH₂–。

47. The compound of any one of claims 1-24 and 40-43, wherein Z₁is-NH (CO) -, - (CO) NH-or-CH₂NH(CO)–。

48. The compound of any one of claims 1-24 and 40-43, wherein Z₁is-CH₂NH–。

49. The compound of any one of claims 1-24 and 40-43, wherein Z₁is-NHCH₂-or-NHCH₂CH₂–。

50. The compound of any one of claims 1-24 and 40-49, wherein Z₂is-NH-.

51. The compound of any one of claims 1-24 and 40-49, wherein Z₂is-O-.

52. The compound of any one of claims 1-24 and 40-49, wherein Z₂is-CH₂–。

53. The compound of any one of claims 1-24 and 40-49, wherein Z₂is-NH (CO) -or- (CO) NH-.

54. The compound of any one of claims 1-24 and 40-49, wherein Z₂Is- (CO) NH–。

55. The compound of any one of claims 1-24 and 40-49, wherein Z₂is-CH₂NH–。

56. The compound of any one of claims 1-24 and 40-49, wherein Z₂is-NHCH₂-or-NHCH₂CH₂–。

57. The compound of any one of claims 1-24 and 40-56, wherein each R₄Independently is unsubstituted C₁-C₄An alkylene group.

58. The compound of claim 57, wherein each R₄Independently is unsubstituted C₁-C₂An alkylene group.

59. The compound of any one of claims 1-24 and 40-58, wherein t is 1.

60. The compound of any one of claims 1-24 and 40-58, wherein t is 2.

61. The compound of any one of claims 1-24 and 40-58, wherein t is 3.

62. The compound of any one of claims 1-24 and 40-58, wherein t is 4.

63. The compound of any one of claims 1-24 and 40-58, wherein t is 5.

64. The compound of any one of claims 1-24 and 40-58, wherein t is 6.

65. The compound of claim 1, having a structural formula selected from the group consisting of:

or a pharmaceutically acceptable salt of any of the foregoing.

66. A pharmaceutical composition comprising a compound of any one of claims 1-65, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

67. A method of inhibiting cytokine activity, comprising contacting a cell with an effective amount of a compound of any one of claims 1-65, or a pharmaceutically acceptable salt thereof.

68. The method of claim 67, wherein the cytokine is selected from the group consisting of IL-1 β, IL-2, IL-6, and TNF α.

69. The method of any one of claims 67-68, wherein the cytokine is TNF α.

70. A method of inhibiting aiolos activity, comprising contacting a cell with an effective amount of a compound of any one of claims 1-65, or a pharmaceutically acceptable salt thereof.

71. A method of inhibiting ikaros activity comprising contacting a cell with an effective amount of a compound of any one of claims 1-65, or a pharmaceutically acceptable salt thereof.

72. A method of inhibiting hellios activity comprising contacting a cell with an effective amount of a compound of any one of claims 1-65, or a pharmaceutically acceptable salt thereof.

73. A method of inhibiting CK-1 α activity comprising contacting a cell with an effective amount of a compound of any one of claims 1-65, or a pharmaceutically acceptable salt thereof.

74. The method of any one of claims 67-73, wherein the cell is a cancer cell.

75. The method of any one of claims 67-74, wherein the cell is a small cell lung cancer cell, a non-small cell lung cancer cell, a breast cancer cell, a prostate cancer cell, a head and neck cancer cell, a pancreatic cancer cell, a colon cancer cell, a rectal cancer cell, a teratoma cell, an ovarian cancer cell, an endometrial cancer cell, a brain cancer cell, a retinoblastoma cell, a leukemia cell, a skin cancer cell, a melanoma cell, a squamous cell carcinoma cell, an liposarcoma cell, a lymphoma cell, a multiple myeloma cell, a testicular cancer cell, a liver cancer cell, an esophageal cancer cell, a renal cancer cell, an astrocyte proliferating cell, a relapsed/refractory multiple myeloma cell, or a neuroblastoma cell.

76. A method of treating, ameliorating, or preventing a disease, disorder, or condition associated with a protein selected from the group consisting of cytokines, aiolos, ikaros, helios, CK1 α, and a combination of any of the foregoing in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-65, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 66.

77. The method of claim 76, wherein the disease, disorder, or condition is a cancer selected from a hematologic malignancy and a solid tumor.

78. The method of any one of claims 76-77, wherein the disease, disorder, or condition is a cancer selected from small cell lung cancer, non-small cell lung cancer, breast cancer, prostate cancer, head and neck cancer, pancreatic cancer, colon cancer, rectal cancer, teratomas, ovarian cancer, endometrial cancer, brain cancer, retinoblastoma, leukemia, skin cancer, melanoma, squamous cell carcinoma, liposarcoma, lymphoma, multiple myeloma, testicular cancer, liver cancer, esophageal cancer, kidney cancer, astrocytosis, relapsed/refractory multiple myeloma, and neuroblastoma.

79. The method of claim 76, wherein the disease, disorder, or condition is selected from inflammation, fibromyalgia, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, uveitis, inflammatory lung disease, chronic obstructive pulmonary disease, and Alzheimer's disease.

80. The method of claim 79, wherein the disease, disorder, or condition is selected from fibromyalgia, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis.

81. The method of any one of claims 76-80, wherein the protein is a cytokine.

82. The method of any one of claims 76-81, wherein the protein is selected from the group consisting of IL-1 β, IL-2, IL-6, and TNF α.

83. The method of any one of claims 76-82, wherein the protein is IL-1 β.

84. The method of any one of claims 76-82, wherein the protein is IL-2.

85. The method of any one of claims 76-82, wherein the protein is IL-6.

86. The method of any one of claims 76-82, wherein the protein is TNF α.

87. The method of any one of claims 76-80, wherein the protein is aiolos.

88. The method of any one of claims 76-80, wherein the protein is ikaros.

89. The method of any one of claims 76-80, wherein the protein is helios.

90. The method of any one of claims 76-80, wherein the protein is CK1 α.

91. The method of any one of claims 76-80, wherein the protein is two of IL-1 β, IL-2, IL-6, TNF α, aiolos, ikaros, helios, and CK1 α.

92. The method of any one of claims 76-91, wherein the protein is overexpressed.

93. The method of any one of claims 76-92, wherein the protein is wild-type.

94. The method of any one of claims 76-92, wherein the protein is a mutant form of a protein.